Cancer epigenetics is the study of
epigenetic
In biology, epigenetics is the study of stable phenotypic changes (known as ''marks'') that do not involve alterations in the DNA sequence. The Greek prefix '' epi-'' ( "over, outside of, around") in ''epigenetics'' implies features that are "o ...
modifications to the DNA of
cancer cell
Cancer cells are cells that divide continually, forming solid tumors or flooding the blood with abnormal cells. Cell division is a normal process used by the body for growth and repair. A parent cell divides to form two daughter cells, and these d ...
s that do not involve a change in the nucleotide sequence, but instead involve a change in the way the genetic code is expressed. Epigenetic mechanisms are necessary to maintain normal sequences of tissue specific gene expression and are crucial for normal development. They may be just as important, if not even more important, than
genetic mutations
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mit ...
in a cell's transformation to cancer. The disturbance of epigenetic processes in cancers, can lead to a loss of
expression of genes
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product that enables it to produce end products, protein or non-coding RNA, and ultimately affect a phenotype, as the final effect. Th ...
that occurs about 10 times more frequently by transcription silencing (caused by epigenetic promoter hypermethylation of
CpG islands
The CpG sites or CG sites are regions of DNA where a cytosine nucleotide is followed by a guanine nucleotide in the linear sequence of bases along its 5' → 3' direction. CpG sites occur with high frequency in genomic regions called CpG isl ...
) than by mutations. As Vogelstein et al. points out, in a colorectal cancer there are usually about 3 to 6 driver mutations and 33 to 66
hitchhiker
Hitchhiking (also known as thumbing, autostop or hitching) is a means of transportation that is gained by asking individuals, usually strangers, for a ride in their car or other vehicle. The ride is usually, but not always, free.
Nomads have ...
or passenger mutations.
However, in colon tumors compared to adjacent normal-appearing colonic mucosa, there are about 600 to 800 heavily methylated CpG islands in the promoters of genes in the tumors while these CpG islands are not methylated in the adjacent mucosa.
Manipulation of epigenetic alterations holds great promise for cancer prevention, detection, and therapy.
In different types of cancer, a variety of epigenetic mechanisms can be perturbed, such as the silencing of
tumor suppressor gene
A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results in a loss or red ...
s and
activation
Activation, in chemistry and biology, is the process whereby something is prepared or excited for a subsequent reaction.
Chemistry
In chemistry, "activation" refers to the reversible transition of a molecule into a nearly identical chemical or ...
of
oncogene
An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels. s by altered
CpG island
The CpG sites or CG sites are regions of DNA where a cytosine nucleotide is followed by a guanine nucleotide in the linear sequence of bases along its 5' → 3' direction. CpG sites occur with high frequency in genomic regions called CpG isl ...
methylation
In the chemical sciences, methylation denotes the addition of a methyl group on a substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replacing a hydrogen atom. These t ...
patterns,
histone
In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei. They act as spools around which DNA winds to create structural units called nucleosomes. Nucleosomes in turn are wr ...
modifications, and dysregulation of
DNA binding protein
DNA-binding proteins are proteins that have DNA-binding domains and thus have a specific or general affinity for single- or double-stranded DNA. Sequence-specific DNA-binding proteins generally interact with the major groove of B-DNA, becaus ...
s. There are several medications which have epigenetic impact, that are now used in a number of these diseases.
Mechanisms
DNA methylation
![DNA methylation](https://upload.wikimedia.org/wikipedia/commons/8/80/DNA_methylation.jpg)
In somatic cells, patterns of DNA methylation are in general transmitted to daughter cells with high fidelity.
Typically, this methylation only occurs at cytosines that are located 5' to guanosine in the CpG dinucleotides of higher order eukaryotes. However, epigenetic
DNA methylation
DNA methylation is a biological process by which methyl groups are added to the DNA molecule. Methylation can change the activity of a DNA segment without changing the sequence. When located in a gene promoter, DNA methylation typically acts t ...
differs between normal cells and tumor cells in humans. The "normal"
CpG methylation profile is often inverted in cells that become tumorigenic.
In normal cells,
CpG island
The CpG sites or CG sites are regions of DNA where a cytosine nucleotide is followed by a guanine nucleotide in the linear sequence of bases along its 5' → 3' direction. CpG sites occur with high frequency in genomic regions called CpG isl ...
s preceding
gene promoter
In genetics, a promoter is a sequence of DNA to which proteins bind to initiate transcription of a single RNA transcript from the DNA downstream of the promoter. The RNA transcript may encode a protein (mRNA), or can have a function in and of i ...
s are generally unmethylated, and tend to be transcriptionally active, while other individual CpG
dinucleotide
Nucleotides are organic molecules consisting of a nucleoside and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecules with ...
s throughout the genome tend to be methylated. However, in cancer cells,
CpG island
The CpG sites or CG sites are regions of DNA where a cytosine nucleotide is followed by a guanine nucleotide in the linear sequence of bases along its 5' → 3' direction. CpG sites occur with high frequency in genomic regions called CpG isl ...
s preceding
tumor suppressor gene
A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results in a loss or red ...
promoters are often hypermethylated, while CpG methylation of oncogene promoter regions and parasitic
repeat sequences
Repeated sequences (also known as repetitive elements, repeating units or repeats) are short or long patterns of nucleic acids (DNA or RNA) that occur in multiple copies throughout the genome. In many organisms, a significant fraction of the genom ...
is often decreased.
Hypermethylation of tumor suppressor gene promoter regions can result in silencing of those genes. This type of epigenetic mutation allows cells to grow and reproduce uncontrollably, leading to tumorigenesis.
The addition of methyl groups to cytosines causes the DNA to coil tightly around the histone proteins, resulting in DNA that can not undergo transcription (transcriptionally silenced DNA). Genes commonly found to be transcriptionally silenced due to promoter hypermethylation include: Cyclin-dependent kinase inhibitor
p16
p16 (also known as p16INK4a, cyclin-dependent kinase inhibitor 2A, CDKN2A, multiple tumor suppressor 1 and numerous other synonyms), is a protein that slows cell division by slowing the progression of the cell cycle from the G1 phase to the S p ...
, a cell-cycle inhibitor;
MGMT
MGMT () is an American indie rock band formed in 2002 in Middletown, Connecticut. It was founded by multi-instrumentalists Andrew VanWyngarden and Ben Goldwasser. Alongside VanWyngarden and Goldwasser, MGMT's live lineup currently consists of ...
, a
DNA repair
DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA dam ...
gene;
APC, a cell cycle regulator;
MLH1
DNA mismatch repair protein Mlh1 or MutL protein homolog 1 is a protein that in humans is encoded by the MLH1 gene located on chromosome 3. It is a gene commonly associated with hereditary nonpolyposis colorectal cancer. Orthologs of human MLH1 h ...
, a DNA-repair gene; and
BRCA1
Breast cancer type 1 susceptibility protein is a protein that in humans is encoded by the ''BRCA1'' () gene. Orthologs are common in other vertebrate species, whereas invertebrate genomes may encode a more distantly related gene. ''BRCA1'' is a h ...
, another DNA-repair gene.
Indeed, cancer cells can become addicted to the transcriptional silencing, due to promoter hypermethylation, of some key tumor suppressor genes, a process known as epigenetic addiction.
Hypomethylation of CpG dinucleotides in other parts of the genome leads to
chromosome instability due to mechanisms such as loss of imprinting and reactivation of
transposable element
A transposable element (TE, transposon, or jumping gene) is a nucleic acid sequence in DNA that can change its position within a genome, sometimes creating or reversing mutations and altering the cell's genetic identity and genome size. Transp ...
s.
Loss of imprinting of
insulin-like growth factor
The insulin-like growth factors (IGFs) are proteins with high sequence similarity to insulin. IGFs are part of a complex system that cells use to communicate with their physiologic environment. This complex system (often referred to as the IGF "a ...
gene (IGF2) increases risk of
colorectal cancer
Colorectal cancer (CRC), also known as bowel cancer, colon cancer, or rectal cancer, is the development of cancer from the colon or rectum (parts of the large intestine). Signs and symptoms may include blood in the stool, a change in bowel m ...
and is associated with
Beckwith-Wiedemann syndrome which significantly increases the risk of cancer for newborns.
In healthy cells, CpG dinucleotides of lower densities are found within coding and
non-coding
Non-coding DNA (ncDNA) sequences are components of an organism's DNA that do not encode protein sequences. Some non-coding DNA is transcribed into functional non-coding RNA molecules (e.g. transfer RNA, microRNA, piRNA, ribosomal RNA, and regula ...
intergenic regions. Expression of some repetitive sequences and meiotic recombination at
centromere
The centromere links a pair of sister chromatids together during cell division. This constricted region of chromosome connects the sister chromatids, creating a short arm (p) and a long arm (q) on the chromatids. During mitosis, spindle fibers a ...
s are repressed through methylation
The entire genome of a cancerous cell contains significantly less
methylcytosine than the genome of a healthy cell. In fact, cancer cell genomes have 20-50% less methylation at individual CpG dinucleotides across the genome.
CpG islands found in promoter regions are usually protected from DNA methylation. In cancer cells CpG islands are hypomethylated The regions flanking CpG islands called CpG island shores are where most DNA methylation occurs in the CpG dinucleotide context. Cancer cells are deferentially methylated at CpG island shores. In cancer cells, hypermethylation in the CpG island shores move into CpG islands, or hypomethylation of CpG islands move into CpG island shores eliminating sharp epigenetic boundaries between these genetic elements. In cancer cells "global hypomethylation" due to disruption in
DNA methyltransferase
In biochemistry, the DNA methyltransferase (DNA MTase, DNMT) family of enzymes catalyze the transfer of a methyl group to DNA. DNA methylation serves a wide variety of biological functions. All the known DNA methyltransferases use S-adenosyl m ...
s (DNMTs) may promote
mitotic recombination
Mitotic recombination is a type of genetic recombination that may occur in somatic cells during their preparation for mitosis in both sexual and asexual organisms. In asexual organisms, the study of mitotic recombination is one way to understand ...
and
chromosome rearrangement
In genetics, a chromosomal rearrangement is a mutation that is a type of chromosome abnormality involving a change in the structure of the native chromosome. Such changes may involve several different classes of events, like Deletion (genetics), de ...
, ultimately resulting in
aneuploidy
Aneuploidy is the presence of an abnormal number of chromosomes in a cell, for example a human cell having 45 or 47 chromosomes instead of the usual 46. It does not include a difference of one or more complete sets of chromosomes. A cell with any ...
when the chromosomes fail to separate properly during
mitosis
In cell biology, mitosis () is a part of the cell cycle in which replicated chromosomes are separated into two new nuclei. Cell division by mitosis gives rise to genetically identical cells in which the total number of chromosomes is mainta ...
.
CpG island methylation is important in regulation of gene expression, yet cytosine methylation can lead directly to destabilizing genetic mutations and a precancerous cellular state. Methylated cytosines make
hydrolysis
Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution reaction, substitution, elimination reaction, elimination, and solvation reactions in which water ...
of the
amine group
In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituent ...
and spontaneous conversion to
thymine
Thymine () ( symbol T or Thy) is one of the four nucleobases in the nucleic acid of DNA that are represented by the letters G–C–A–T. The others are adenine, guanine, and cytosine. Thymine is also known as 5-methyluracil, a pyrimidine nu ...
more favorable. They can cause aberrant recruitment of
chromatin
Chromatin is a complex of DNA and protein found in eukaryotic cells. The primary function is to package long DNA molecules into more compact, denser structures. This prevents the strands from becoming tangled and also plays important roles in r ...
proteins. Cytosine methylations change the amount of UV light absorption of the nucleotide base, creating
pyrimidine dimer
Pyrimidine dimers are molecular lesions formed from thymine or cytosine bases in DNA via photochemical reactions, commonly associated with direct DNA damage. Ultraviolet light (UV; particularly UVB) induces the formation of covalent linkages betwe ...
s. When mutation results in loss of
heterozygosity
Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism.
Mo ...
at tumor suppressor gene sites, these genes may become inactive. Single base pair mutations during replication can also have detrimental effects.
Histone modification
Eukaryotic DNA has a complex structure. It is generally wrapped around special proteins called
histone
In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei. They act as spools around which DNA winds to create structural units called nucleosomes. Nucleosomes in turn are wr ...
s to form a structure called a
nucleosome
A nucleosome is the basic structural unit of DNA packaging in eukaryotes. The structure of a nucleosome consists of a segment of DNA wound around eight histone proteins and resembles thread wrapped around a spool. The nucleosome is the fundamen ...
. A nucleosome consists of 2 sets of 4 histones:
H2A,
H2B,
H3, and
H4. Additionally,
histone H1
Histone H1 is one of the five main histone protein families which are components of chromatin in eukaryotic cells. Though highly conserved, it is nevertheless the most variable histone in sequence across species.
Structure
Metazoan H1 prote ...
contributes to
DNA packaging outside of the nucleosome. Certain histone modifying enzymes can add or remove functional groups to the histones, and these modifications influence the level of transcription of the genes wrapped around those histones and the level of DNA replication. Histone modification profiles of healthy and cancerous cells tend to differ.
In comparison to healthy cells, cancerous cells exhibit decreased monoacetylated and trimethylated forms of
histone H4
Histone H4 is one of the five main histone proteins involved in the structure of chromatin in eukaryote, eukaryotic cells. Featuring a main globular domain and a long N-terminus, N-terminal tail, H4 is involved with the structure of the nucleos ...
(decreased H4ac and H4me3).
Additionally, mouse models have shown that a decrease in histone H4R3 asymmetric dimethylation (H4R3me2a) of the
p19ARF promoter is correlated with more advanced cases of tumorigenesis and metastasis.
In mouse models, the loss of histone H4 acetylation and trimethylation increases as tumor growth continues.
Loss of histone H4 Lysine 16 acetylation (
H4K16ac), which is a mark of aging at the
telomere
A telomere (; ) is a region of repetitive nucleotide sequences associated with specialized proteins at the ends of linear chromosomes. Although there are different architectures, telomeres, in a broad sense, are a widespread genetic feature mos ...
s, specifically loses its acetylation. Some scientists hope this particular loss of histone acetylation might be battled with a
histone deacetylase (HDAC) inhibitor specific for
SIRT1
Sirtuin 1, also known as NAD-dependent deacetylase sirtuin-1, is a protein that in humans is encoded by the SIRT1 gene.
SIRT1 stands for sirtuin (silent mating type information regulation 2 homolog) 1 (''S. cerevisiae''), referring to the fact t ...
, an HDAC specific for H4K16.
Other histone marks associated with
tumorigenesis
Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abno ...
include increased deacetylation (decreased acetylation) of histones H3 and H4, decreased trimethylation of histone H3 Lysine 4 (
H3K4me3
H3K4me3 is an epigenetic modification to the DNA packaging protein Histone H3 that indicates tri-methylation at the 4th lysine residue of the histone H3 protein and is often involved in the regulation of gene expression. The name denotes the add ...
), and increased monomethylation of histone H3 Lysine 9 (
H3K9me) and trimethylation of histone H3 Lysine 27 (
H3K27me3
H3K27me3 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the tri-methylation of lysine 27 on histone H3 protein.
This tri-methylation is associated with the downregulation of nearby genes via t ...
). These histone modifications can silence tumor suppressor genes despite the drop in methylation of the gene's CpG island (an event that normally activates genes).
Some research has focused on blocking the action of
BRD4
Bromodomain-containing protein 4 is a protein that in humans is encoded by the ''BRD4'' gene.
BRD4 is a member of the BET (bromodomain and extra terminal domain) family, which also includes BRD2, BRD3, and BRDT. BRD4, similar to other BET famil ...
on acetylated histones, which has been shown to increase the expression of the
Myc
''Myc'' is a family of regulator genes and proto-oncogenes that code for transcription factors. The ''Myc'' family consists of three related human genes: ''c-myc'' (MYC), ''l-myc'' ( MYCL), and ''n-myc'' (MYCN). ''c-myc'' (also sometimes refe ...
protein, implicated in several cancers. The development process of the drug to bind to BRD4 is noteworthy for the collaborative, open approach the team is taking.
The tumor suppressor gene
p53
p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often s ...
regulates
DNA repair
DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA dam ...
and can induce apoptosis in dysregulated cells. E Soto-Reyes and F Recillas-Targa elucidated the importance of the
CTCF
Transcriptional repressor CTCF also known as 11-zinc finger protein or CCCTC-binding factor is a transcription factor that in humans is encoded by the ''CTCF'' gene. CTCF is involved in many cellular processes, including transcriptional regulatio ...
protein in regulating p53 expression.
CTCF, or CCCTC binding factor, is a
zinc finger
A zinc finger is a small protein structural motif that is characterized by the coordination of one or more zinc ions (Zn2+) in order to stabilize the fold. It was originally coined to describe the finger-like appearance of a hypothesized struct ...
protein that insulates the p53
promoter from accumulating repressive histone marks. In certain types of cancer cells, the CTCF protein does not bind normally, and the p53 promoter accumulates repressive histone marks, causing p53 expression to decrease.
Mutations in the epigenetic machinery itself may occur as well, potentially responsible for the changing epigenetic profiles of cancerous cells. The
histone
In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei. They act as spools around which DNA winds to create structural units called nucleosomes. Nucleosomes in turn are wr ...
variants of the H2A family are highly conserved in mammals, playing critical roles in regulating many nuclear processes by altering
chromatin
Chromatin is a complex of DNA and protein found in eukaryotic cells. The primary function is to package long DNA molecules into more compact, denser structures. This prevents the strands from becoming tangled and also plays important roles in r ...
structure. One of the key H2A variants, H2A.X, marks DNA damage, facilitating the recruitment of DNA repair proteins to restore genomic integrity. Another variant, H2A.Z, plays an important role in both gene activation and repression. A high level of H2A.Z expression is detected in many cancers and is significantly associated with cellular proliferation and genomic instability.
Histone variant macroH2A1 is important in the pathogenesis of many types of cancers, for instance in hepatocellular carcinoma. Other mechanisms include a decrease in H4K16ac may be caused by either a decrease in activity of a
histone acetyltransferase
Histone acetyltransferases (HATs) are enzymes that acetylate conserved lysine amino acids on histone proteins by transferring an acetyl group from acetyl-CoA to form ε-''N''-acetyllysine. DNA is wrapped around histones, and, by transferring an ...
s (HATs) or an increase in deacetylation by SIRT1.
Likewise, an inactivating
frameshift
Ribosomal frameshifting, also known as translational frameshifting or translational recoding, is a biological phenomenon that occurs during translation that results in the production of multiple, unique proteins from a single mRNA. The process can ...
mutation in
HDAC2
Histone deacetylase 2 (HDAC2) is an enzyme that in humans is encoded by the ''HDAC2'' gene. It belongs to the histone deacetylase class of enzymes responsible for the removal of acetyl groups from lysine residues at the N-terminal region of the co ...
, a
histone deacetylase that acts on many histone-tail
lysine
Lysine (symbol Lys or K) is an α-amino acid that is a precursor to many proteins. It contains an α-amino group (which is in the protonated form under biological conditions), an α-carboxylic acid group (which is in the deprotonated −C ...
s, has been associated with cancers showing altered histone acetylation patterns.
These findings indicate a promising mechanism for altering epigenetic profiles through enzymatic inhibition or enhancement.
DNA damage
DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA da ...
, caused by UV light,
ionizing radiation
Ionizing radiation (or ionising radiation), including nuclear radiation, consists of subatomic particles or electromagnetic waves that have sufficient energy to ionize atoms or molecules by detaching electrons from them. Some particles can travel ...
, environmental toxins, and metabolic chemicals, can also lead to genomic instability and cancer. The DNA damage response to double strand
DNA breaks (DSB) is mediated in part by histone modifications. At a DSB,
MRE11
Double-strand break repair protein MRE11 is an enzyme that in humans is encoded by the ''MRE11'' gene. The gene has been designated ''MRE11A'' to distinguish it from the pseudogene ''MRE11B'' that is nowadays named ''MRE11P1''.
Function
This ge ...
-
RAD50
DNA repair protein RAD50, also known as RAD50, is a protein that in humans is encoded by the ''RAD50'' gene.
Function
The protein encoded by this gene is highly similar to ''Saccharomyces cerevisiae'' Rad50, a protein involved in DNA double- ...
-
NBS1
Nibrin, also known as NBN or NBS1, is a protein which in humans is encoded by the ''NBN'' gene.
Function
Nibrin is a protein associated with the repair of double strand breaks (DSBs) which pose serious damage to a genome. It is a 754 amino ac ...
(MRN) protein complex recruits
ataxia telangiectasia
Ataxia is a neurological sign consisting of lack of voluntary Motor coordination, coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in eye movements. Ataxia is a clinical manifestation indicati ...
mutated (ATM) kinase which phosphorylates Serine 129 of Histone 2A. MDC1, mediator of DNA damage checkpoint 1, binds to the phosphopeptide, and phosphorylation of
H2AX
H2A histone family member X (usually abbreviated as H2AX) is a type of histone protein from the H2A family encoded by the ''H2AFX'' gene. An important phosphorylated form is γH2AX (S139), which forms when double-strand breaks appear.
In humans ...
may spread by a positive feedback loop of MRN-ATM recruitment and phosphorylation.
TIP60 acetylates the
γH2AX, which is then
polyubiquitylated.
RAP80, a subunit of the DNA repair breast cancer type 1 susceptibility protein complex (
BRCA1
Breast cancer type 1 susceptibility protein is a protein that in humans is encoded by the ''BRCA1'' () gene. Orthologs are common in other vertebrate species, whereas invertebrate genomes may encode a more distantly related gene. ''BRCA1'' is a h ...
-A), binds
ubiquitin
Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Fo ...
attached to histones. BRCA1-A activity arrests the
cell cycle
The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA (DNA replication) and some of its organelles, and subs ...
at the
G2/M checkpoint, allowing time for DNA repair, or
apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
may be initiated.
MicroRNA gene silencing
In mammals,
microRNA
MicroRNA (miRNA) are small, single-stranded, non-coding RNA molecules containing 21 to 23 nucleotides. Found in plants, animals and some viruses, miRNAs are involved in RNA silencing and post-transcriptional regulation of gene expression. miRN ...
s (miRNAs) regulate about 60% of the
transcriptional activity of protein-encoding genes.
Some miRNAs also undergo methylation-associated silencing in cancer cells.
Let-7 and miR15/16 play important roles in down-regulating
RAS
Ras or RAS may refer to:
Arts and media
* RAS Records Real Authentic Sound, a reggae record label
* Rundfunk Anstalt Südtirol, a south Tyrolese public broadcasting service
* Rás 1, an Icelandic radio station
* Rás 2, an Icelandic radio stati ...
and
BCL2
Bcl-2 (B-cell lymphoma 2), encoded in humans by the ''BCL2'' gene, is the founding member of the Bcl-2 family of regulator proteins that regulate cell death ( apoptosis), by either inhibiting (anti-apoptotic) or inducing (pro-apoptotic) apoptosis ...
oncogenes
An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels. , and their silencing occurs in cancer cells.
Decreased expression of miR-125b1, a miRNA that functions as a
tumor suppressor
A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results in a loss or red ...
, was observed in prostate,
ovarian
The ovary is an organ in the female reproductive system that produces an ovum. When released, this travels down the fallopian tube into the uterus, where it may become fertilized by a sperm. There is an ovary () found on each side of the body ...
, breast and
glial cell cancers. In vitro experiments have shown that miR-125b1 targets two genes,
HER2/neu
Receptor tyrosine-protein kinase erbB-2 is a protein that in humans is encoded by the ''ERBB2'' gene. ERBB is abbreviated from erythroblastic oncogene B, a gene originally isolated from the avian genome. The human protein is also frequently refer ...
and
ESR1
Estrogen receptor alpha (ERα), also known as NR3A1 (nuclear receptor subfamily 3, group A, member 1), is one of two main types of estrogen receptor, a nuclear receptor (mainly found as a chromatin-binding protein)
that is activated by the sex ...
, that are linked to breast cancer. DNA methylation, specifically hypermethylation, is one of the main ways that the miR-125b1 is epigenetically silenced. In patients with breast cancer, hypermethylation of CpG islands located proximal to the transcription start site was observed. Loss of
CTCF
Transcriptional repressor CTCF also known as 11-zinc finger protein or CCCTC-binding factor is a transcription factor that in humans is encoded by the ''CTCF'' gene. CTCF is involved in many cellular processes, including transcriptional regulatio ...
binding and an increase in repressive histone marks, H3K9me3 and H3K27me3, correlates with
DNA methylation
DNA methylation is a biological process by which methyl groups are added to the DNA molecule. Methylation can change the activity of a DNA segment without changing the sequence. When located in a gene promoter, DNA methylation typically acts t ...
and miR-125b1 silencing. Mechanistically, CTCF may function as a boundary element to stop the spread of DNA methylation. Results from experiments conducted by Soto-Reyes et al.
indicate a negative effect of methylation on the function and expression of miR-125b1. Therefore, they concluded that DNA methylation has a part in silencing the gene. Furthermore, some miRNA's are epigenetically silenced early on in breast cancer, and therefore these miRNA's could potentially be useful as tumor markers.
The epigenetic silencing of miRNA genes by aberrant DNA methylation is a frequent event in cancer cells; almost one third of miRNA promoters active in normal mammary cells were found hypermethylated in breast cancer cells - that is a several fold greater proportion than is usually observed for protein coding genes.
Metabolic recoding of epigenetics in cancer
Dysregulation of metabolism allows tumor cells to generate needed building blocks as well as to modulate epigenetic marks to support cancer initiation and progression. Cancer-induced metabolic changes alter the epigenetic landscape, especially modifications on histones and DNA, thereby promoting malignant transformation, adaptation to inadequate nutrition, and metastasis. In order to satisfy the biosynthetic demands of cancer cells, metabolic pathways are altered by manipulating oncogenes and tumor suppressive genes concurrently.
The accumulation of certain metabolites in cancer can target epigenetic enzymes to globally alter the epigenetic landscape. Cancer-related metabolic changes lead to locus-specific recoding of epigenetic marks. Cancer epigenetics can be precisely reprogramed by cellular metabolism through 1) dose-responsive modulation of cancer epigenetics by metabolites; 2) sequence-specific recruitment of metabolic enzymes; and 3) targeting of epigenetic enzymes by nutritional signals.
In addition to modulating metabolic programming on a molecular level, there are microenvironmental factors that can influence and effect metabolic recoding. These influences include nutritional, inflammatory, and the immune response of malignant tissues.
MicroRNA and DNA repair
DNA damage appears to be the primary underlying cause of cancer.
If DNA repair is deficient, DNA damage tends to accumulate. Such excess DNA damage can increase
mutational
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...
errors during
DNA replication
In molecular biology, DNA replication is the biological process of producing two identical replicas of DNA from one original DNA molecule. DNA replication occurs in all living organisms acting as the most essential part for biological inheritanc ...
due to error-prone
translesion synthesis
DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA dama ...
. Excess DNA damage can also increase
epigenetic
In biology, epigenetics is the study of stable phenotypic changes (known as ''marks'') that do not involve alterations in the DNA sequence. The Greek prefix '' epi-'' ( "over, outside of, around") in ''epigenetics'' implies features that are "o ...
alterations due to errors during DNA repair.
Such mutations and epigenetic alterations can give rise to
cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
(see
malignant neoplasms
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal bl ...
).
Germ line
In biology and genetics, the germline is the population of a multicellular organism's cells that pass on their genetic material to the progeny (offspring). In other words, they are the cells that form the egg, sperm and the fertilised egg. They ...
mutations in DNA repair genes cause only 2–5% of
colon cancer
Colorectal cancer (CRC), also known as bowel cancer, colon cancer, or rectal cancer, is the development of cancer from the colon or rectum (parts of the large intestine). Signs and symptoms may include blood in the stool, a change in bowel mo ...
cases. However, altered expression of microRNAs, causing DNA repair deficiencies, are frequently associated with cancers and may be an important
causal
Causality (also referred to as causation, or cause and effect) is influence by which one event, process, state, or object (''a'' ''cause'') contributes to the production of another event, process, state, or object (an ''effect'') where the cau ...
factor for these cancers.
Over-expression of certain miRNAs may directly reduce expression of specific DNA repair proteins. Wan et al. referred to 6 DNA repair genes that are directly targeted by the miRNAs indicated in parentheses: ''ATM'' (miR-421), ''RAD52'' (miR-210, miR-373), ''RAD23B'' (miR-373), ''MSH2'' (miR-21), ''BRCA1'' (miR-182) and ''P53'' (miR-504, miR-125b). More recently, Tessitore et al.
listed further DNA repair genes that are directly targeted by additional miRNAs, including ''ATM'' (miR-18a, miR-101), ''DNA-PK'' (miR-101), ''ATR'' (miR-185), ''Wip1'' (miR-16), ''MLH1, MSH2'' and ''MSH6'' (miR-155), ''ERCC3'' and ''ERCC4'' (miR-192) and ''UNG2'' (mir-16, miR-34c and miR-199a). Of these miRNAs, miR-16, miR-18a, miR-21, miR-34c, miR-125b, miR-101, miR-155, miR-182, miR-185 and miR-192 are among those identified by Schnekenburger and Diederich
as over-expressed in colon cancer through epigenetic hypomethylation. Over expression of any one of these miRNAs can cause reduced expression of its target DNA repair gene.
Up to 15% of the
MLH1
DNA mismatch repair protein Mlh1 or MutL protein homolog 1 is a protein that in humans is encoded by the MLH1 gene located on chromosome 3. It is a gene commonly associated with hereditary nonpolyposis colorectal cancer. Orthologs of human MLH1 h ...
-deficiencies in sporadic colon cancers appeared to be due to over-expression of the microRNA
miR-155
MiR-155 is a microRNA that in humans is encoded by the ''MIR155'' host gene or ''MIR155HG''. MiR-155 plays a role in various physiological and pathological processes. Exogenous molecular control ''in vivo'' of miR-155 expression may inhibit mali ...
, which represses MLH1 expression.
However, the majority of 68 sporadic colon cancers with reduced expression of the
DNA mismatch repair
DNA mismatch repair (MMR) is a system for recognizing and repairing erroneous insertion, deletion, and mis-incorporation of nucleobase, bases that can arise during DNA replication and Genetic recombination, recombination, as well as DNA repair, r ...
protein
MLH1
DNA mismatch repair protein Mlh1 or MutL protein homolog 1 is a protein that in humans is encoded by the MLH1 gene located on chromosome 3. It is a gene commonly associated with hereditary nonpolyposis colorectal cancer. Orthologs of human MLH1 h ...
were found to be deficient due to
epigenetic methylation of the CpG island of the ''MLH1'' gene.
In 28% of glioblastomas, the MGMT DNA repair protein is deficient but the ''MGMT'' promoter is not methylated.
In the glioblastomas without methylated ''MGMT'' promoters, the level of microRNA miR-181d is
inversely correlated with protein expression of MGMT and the direct target of miR-181d is the MGMT
mRNA
In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein.
mRNA is ...
3'UTR (the
three prime untranslated region
In molecular genetics, the three prime untranslated region (3′-UTR) is the section of messenger RNA (mRNA) that immediately follows the translation termination codon. The 3′-UTR often contains regulatory regions that post-transcriptionally ...
of MGMT mRNA).
Thus, in 28% of glioblastomas, increased expression of miR-181d and reduced expression of DNA repair enzyme MGMT may be a causal factor. In 29–66%
of
glioblastomas
Glioblastoma, previously known as glioblastoma multiforme (GBM), is one of the most aggressive types of cancer that begin within the brain. Initially, signs and symptoms of glioblastoma are nonspecific. They may include headaches, personality cha ...
, DNA repair is deficient due to epigenetic methylation of the
''MGMT'' gene, which reduces protein expression of MGMT.
High mobility group A (
HMGA
HMGA is a family of high mobility group proteins characterized by an AT-hook. They code for a "small, nonhistone, chromatin-associated protein that has no intrinsic transcriptional activity but can modulate transcription by altering the chromati ...
) proteins, characterized by an
AT-hook, are small, nonhistone, chromatin-associated proteins that can modulate transcription. MicroRNAs control the expression of
HMGA
HMGA is a family of high mobility group proteins characterized by an AT-hook. They code for a "small, nonhistone, chromatin-associated protein that has no intrinsic transcriptional activity but can modulate transcription by altering the chromati ...
proteins, and these proteins (
HMGA1
High-mobility group protein HMG-I/HMG-Y is a protein that in humans is encoded by the ''HMGA1'' gene.
Function
This gene encodes a non-histone chromatin protein involved in many cellular processes, including regulation of inducible gene transc ...
and
HMGA2
High-mobility group AT-hook 2, also known as HMGA2, is a protein that, in humans, is encoded by the ''HMGA2'' gene.
Function
This gene encodes a protein that belongs to the non-histone chromosomal high-mobility group (HMG) protein family. HMG ...
) are architectural chromatin transcription-controlling elements. Palmieri et al.
showed that, in normal tissues, ''HGMA1'' and ''HMGA2'' genes are targeted (and thus strongly reduced in expression) by
miR-15,
miR-16,
miR-26a,
miR-196a2 and
Let-7a.
HMGA expression is almost undetectable in differentiated adult tissues but is elevated in many cancers. HGMA proteins are polypeptides of ~100 amino acid residues characterized by a modular sequence organization. These proteins have three highly positively charged regions, termed
AT hook
The second AT-hook of HMGA1 (black ribbon) bound to the minor-groove of AT-rich DNA. The amino-acid side chains and nucleotides have been hidden.
The AT-hook is a DNA-binding motif present in many proteins, including the high mobility group (H ...
s, that bind the minor groove of AT-rich DNA stretches in specific regions of DNA. Human neoplasias, including thyroid, prostatic, cervical, colorectal, pancreatic and ovarian carcinoma, show a strong increase of HMGA1a and HMGA1b proteins. Transgenic mice with HMGA1 targeted to lymphoid cells develop aggressive lymphoma, showing that high HMGA1 expression is not only associated with cancers, but that the ''HMGA1'' gene can act as an oncogene to cause cancer. Baldassarre et al., showed that HMGA1 protein binds to the promoter region of DNA repair gene ''BRCA1'' and inhibits ''BRCA1'' promoter activity. They also showed that while only 11% of breast tumors had hypermethylation of the ''BRCA1'' gene, 82% of aggressive breast cancers have low BRCA1 protein expression, and most of these reductions were due to chromatin remodeling by high levels of HMGA1 protein.
HMGA2 protein specifically targets the promoter of ''
ERCC1
DNA excision repair protein ERCC-1 is a protein that in humans is encoded by the ''ERCC1'' gene. Together with ERCC4, ERCC1 forms the ERCC1-XPF enzyme complex that participates in DNA repair and DNA recombination.
Many aspects of these two gene ...
'', thus reducing expression of this DNA repair gene. ERCC1 protein expression was deficient in 100% of 47 evaluated colon cancers (though the extent to which HGMA2 was involved is unknown).
Palmieri et al.
showed that each of the miRNAs that target ''HMGA'' genes are drastically reduced in almost all human pituitary adenomas studied, when compared with the normal pituitary gland. Consistent with the down-regulation of these HMGA-targeting miRNAs, an increase in the HMGA1 and HMGA2-specific mRNAs was observed. Three of these microRNAs (miR-16, miR-196a and Let-7a)
have methylated promoters and therefore low expression in colon cancer. For two of these, miR-15 and miR-16, the coding regions are epigenetically silenced in cancer due to
histone deacetylase activity. When these microRNAs are expressed at a low level, then HMGA1 and HMGA2 proteins are expressed at a high level. HMGA1 and HMGA2 target (reduce expression of) ''
BRCA1
Breast cancer type 1 susceptibility protein is a protein that in humans is encoded by the ''BRCA1'' () gene. Orthologs are common in other vertebrate species, whereas invertebrate genomes may encode a more distantly related gene. ''BRCA1'' is a h ...
'' and ''
ERCC1
DNA excision repair protein ERCC-1 is a protein that in humans is encoded by the ''ERCC1'' gene. Together with ERCC4, ERCC1 forms the ERCC1-XPF enzyme complex that participates in DNA repair and DNA recombination.
Many aspects of these two gene ...
'' DNA repair genes. Thus DNA repair can be reduced, likely contributing to cancer progression.
DNA repair pathways
![DNA damage, repair, alteration of repair in cancer](https://upload.wikimedia.org/wikipedia/commons/a/a2/DNA_damage%2C_repair%2C_alteration_of_repair_in_cancer.png)
The chart in this section shows some frequent DNA damaging agents, examples of DNA lesions they cause, and the pathways that deal with these DNA damages. At least 169 enzymes are either directly employed in DNA repair or influence DNA repair processes. Of these, 83 are directly employed in repairing the 5 types of DNA damages illustrated in the chart.
Some of the more well studied genes central to these repair processes are shown in the chart. The gene designations shown in red, gray or cyan indicate genes frequently epigenetically altered in various types of cancers. Wikipedia articles on each of the genes highlighted by red, gray or cyan describe the epigenetic alteration(s) and the cancer(s) in which these epimutations are found. Two broad experimental survey articles also document most of these epigenetic DNA repair deficiencies in cancers.
Red-highlighted genes are frequently reduced or silenced by epigenetic mechanisms in various cancers. When these genes have low or absent expression, DNA damages can accumulate. Replication errors past these damages (see
translesion synthesis
DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA dama ...
) can lead to increased mutations and, ultimately, cancer. Epigenetic repression of DNA repair genes in ''accurate'' DNA repair pathways appear to be central to
carcinogenesis
Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abnor ...
.
The two gray-highlighted genes ''
RAD51'' and ''
BRCA2
''BRCA2'' and BRCA2 () are a human gene and its protein product, respectively. The official symbol (BRCA2, italic for the gene, nonitalic for the protein) and the official name (originally breast cancer 2; currently BRCA2, DNA repair associated) ...
'', are required for
homologous recombination
Homologous recombination is a type of genetic recombination in which genetic information is exchanged between two similar or identical molecules of double-stranded or single-stranded nucleic acids (usually DNA as in cellular organisms but may ...
al repair. They are sometimes epigenetically over-expressed and sometimes under-expressed in certain cancers. As indicated in the Wikipedia articles on
RAD51 and
BRCA2
''BRCA2'' and BRCA2 () are a human gene and its protein product, respectively. The official symbol (BRCA2, italic for the gene, nonitalic for the protein) and the official name (originally breast cancer 2; currently BRCA2, DNA repair associated) ...
, such cancers ordinarily have epigenetic deficiencies in other DNA repair genes. These repair deficiencies would likely cause increased unrepaired DNA damages. The over-expression of ''RAD51'' and ''BRCA2'' seen in these cancers may reflect selective pressures for compensatory ''RAD51'' or ''BRCA2'' over-expression and increased homologous recombinational repair to at least partially deal with such excess DNA damages. In those cases where ''RAD51'' or ''BRCA2'' are under-expressed, this would itself lead to increased unrepaired DNA damages. Replication errors past these damages (see
translesion synthesis
DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA dama ...
) could cause increased mutations and cancer, so that under-expression of ''RAD51'' or ''BRCA2'' would be carcinogenic in itself.
Cyan-highlighted genes are in the
microhomology-mediated end joining
Microhomology-mediated end joining (MMEJ), also known as alternative nonhomologous end-joining (Alt-NHEJ) is one of the pathways for repairing double-strand breaks in DNA. As reviewed by McVey and Lee, the foremost distinguishing property of MMEJ ...
(MMEJ) pathway and are up-regulated in cancer. MMEJ is an additional error-prone ''inaccurate'' repair pathway for double-strand breaks. In MMEJ repair of a double-strand break, an homology of 5-25 complementary base pairs between both paired strands is sufficient to align the strands, but mismatched ends (flaps) are usually present. MMEJ removes the extra nucleotides (flaps) where strands are joined, and then ligates the strands to create an intact DNA double helix. MMEJ almost always involves at least a small deletion, so that it is a mutagenic pathway.
FEN1
Flap endonuclease 1 is an enzyme that in humans is encoded by the ''FEN1'' gene.
Function
The protein encoded by this gene removes 5' overhanging "flaps" (or short sections of single stranded DNA that "hang off" because their nucleotide bases a ...
, the flap endonuclease in MMEJ, is epigenetically increased by promoter hypomethylation and is over-expressed in the majority of cancers of the breast,
prostate,
stomach,
neuroblastomas,
pancreas,
and lung.
PARP1 is also over-expressed when its promoter region
ETS
ETS or ets may refer to:
Climate change, environment and economy
* Emissions trading scheme
** European Union Emission Trading Scheme
Organisations
* European Thermoelectric Society
* Evangelical Theological Society
Education
* École de techno ...
site is epigenetically hypomethylated, and this contributes to progression to endometrial cancer,
BRCA-mutated ovarian cancer,
and BRCA-mutated serous ovarian cancer.
Other genes in the
MMEJ pathway are also over-expressed in a number of cancers (see
MMEJ for summary), and are also shown in blue.
Frequencies of epimutations in DNA repair genes
Deficiencies in DNA repair proteins that function in accurate DNA repair pathways increase the risk of mutation. Mutation rates are strongly increased in cells with mutations in
DNA mismatch repair
DNA mismatch repair (MMR) is a system for recognizing and repairing erroneous insertion, deletion, and mis-incorporation of nucleobase, bases that can arise during DNA replication and Genetic recombination, recombination, as well as DNA repair, r ...
or in
homologous recombination
Homologous recombination is a type of genetic recombination in which genetic information is exchanged between two similar or identical molecules of double-stranded or single-stranded nucleic acids (usually DNA as in cellular organisms but may ...
al repair (HRR).
Individuals with inherited mutations in any of 34 DNA repair genes are at increased risk of cancer (see
DNA repair defects and increased cancer risk).
In sporadic cancers, a deficiency in DNA repair is occasionally found to be due to a mutation in a DNA repair gene, but much more frequently reduced or absent expression of DNA repair genes is due to epigenetic alterations that reduce or silence gene expression. For example, for 113 colorectal cancers examined in sequence, only four had a
missense mutation
In genetics, a missense mutation is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid. It is a type of nonsynonymous substitution.
Substitution of protein from DNA mutations
Missense m ...
in the DNA repair gene
''MGMT'', while the majority had reduced ''MGMT'' expression due to methylation of the ''MGMT'' promoter region (an epigenetic alteration). Similarly, out of 119 cases of mismatch repair-deficient colorectal cancers that lacked DNA repair gene ''PMS2'' expression, PMS2 protein was deficient in 6 due to mutations in the ''PMS2'' gene, while in 103 cases PMS2 expression was deficient because its pairing partner MLH1 was repressed due to promoter methylation (PMS2 protein is unstable in the absence of MLH1).
In the other 10 cases, loss of PMS2 expression was likely due to epigenetic overexpression of the microRNA, miR-155, which down-regulates MLH1.
Epigenetic defects in DNA repair genes are frequent in cancers. In the table, multiple cancers were evaluated for reduced or absent expression of the DNA repair gene of interest, and the frequency shown is the frequency with which the cancers had an epigenetic deficiency of gene expression. Such epigenetic deficiencies likely arise early in
carcinogenesis
Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abnor ...
, since they are also frequently found (though at somewhat lower frequency) in the
field defect surrounding the cancer from which the cancer likely arose (see Table).
It appears that cancers may frequently be initiated by an epigenetic reduction in expression of one or more DNA repair enzymes. Reduced DNA repair likely allows accumulation of DNA damages. Error prone
translesion synthesis
DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA dama ...
past some of these DNA damages may give rise to a mutation with a selective advantage. A clonal patch with a selective advantage may grow and out-compete neighboring cells, forming a
field defect. While there is no obvious
selective advantage for a cell to have reduced DNA repair, the
epimutation
In biology, epigenetics is the study of stable phenotypic changes (known as ''marks'') that do not involve alterations in the DNA sequence. The Greek prefix '' epi-'' ( "over, outside of, around") in ''epigenetics'' implies features that are " ...
of the DNA repair gene may be carried along as a passenger when the cells with the selectively advantageous mutation are replicated. In the cells carrying both the epimutation of the DNA repair gene and the mutation with the selective advantage, further DNA damages will accumulate, and these could, in turn, give rise to further mutations with still greater selective advantages. Epigenetic defects in DNA repair may thus contribute to the characteristic high frequency of mutations in the genomes of cancers, and cause their carcinogenic progression.
Cancers have high levels of
genome instability
Genome instability (also genetic instability or genomic instability) refers to a high frequency of mutations within the genome of a cellular lineage. These mutations can include changes in nucleic acid sequences, chromosomal rearrangements or aneup ...
, associated with a high frequency of
mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...
s. A high frequency of genomic mutations increases the likelihood of particular mutations occurring that activate oncogenes and inactivate tumor suppressor genes, leading to
carcinogenesis
Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abnor ...
. On the basis of
whole genome sequencing
Whole genome sequencing (WGS), also known as full genome sequencing, complete genome sequencing, or entire genome sequencing, is the process of determining the entirety, or nearly the entirety, of the DNA sequence of an organism's genome at a s ...
, cancers are found to have thousands to hundreds of thousands of mutations in their whole genomes.
(Also see
Mutation frequencies in cancers.) By comparison, the mutation frequency in the whole genome between generations for humans (parent to child) is about 70 new mutations per generation. In the protein coding regions of the genome, there are only about 0.35 mutations between parent/child generations (less than one mutated protein per generation). Whole genome sequencing in blood cells for a pair of identical twin 100-year-old centenarians only found 8 somatic differences, though somatic variation occurring in less than 20% of blood cells would be undetected.
While DNA damages may give rise to mutations through error prone
translesion synthesis
DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA dama ...
, DNA damages can also give rise to epigenetic alterations during faulty DNA repair processes.
The DNA damages that accumulate due to epigenetic DNA repair defects can be a source of the increased epigenetic alterations found in many genes in cancers. In an early study, looking at a limited set of transcriptional promoters, Fernandez et al.
examined the DNA methylation profiles of 855 primary tumors. Comparing each tumor type with its corresponding normal tissue, 729 CpG island sites (55% of the 1322 CpG sites evaluated) showed differential DNA methylation. Of these sites, 496 were hypermethylated (repressed) and 233 were hypomethylated (activated). Thus, there is a high level of epigenetic promoter methylation alterations in tumors. Some of these epigenetic alterations may contribute to cancer progression.
Epigenetic carcinogens
A variety of compounds are considered as epigenetic
carcinogens
A carcinogen is any substance, radionuclide, or radiation that promotes carcinogenesis (the formation of cancer). This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes. Several radioactive substan ...
—they result in an increased incidence of tumors, but they do not show
mutagen
In genetics, a mutagen is a physical or chemical agent that permanently changes nucleic acid, genetic material, usually DNA, in an organism and thus increases the frequency of mutations above the natural background level. As many mutations can ca ...
activity (toxic compounds or pathogens that cause tumors incident to increased regeneration should also be excluded). Examples include
diethylstilbestrol
Diethylstilbestrol (DES), also known as stilbestrol or stilboestrol, is a nonsteroidal estrogen medication, which is presently rarely used. In the past, it was widely used for a variety of indications, including pregnancy support for those with a ...
,
arsenite
In chemistry, an arsenite is a chemical compound containing an arsenic oxyanion where arsenic has oxidation state +3. Note that in fields that commonly deal with groundwater chemistry, arsenite is used generically to identify soluble AsIII anions. ...
,
hexachlorobenzene
Hexachlorobenzene, or perchlorobenzene, is an organochloride with the molecular formula C6Cl6. It is a fungicide formerly used as a seed treatment, especially on wheat to control the fungal disease bunt. It has been banned globally under the Sto ...
, and
nickel
Nickel is a chemical element with symbol Ni and atomic number 28. It is a silvery-white lustrous metal with a slight golden tinge. Nickel is a hard and ductile transition metal. Pure nickel is chemically reactive but large pieces are slow to ...
compounds.
Many
teratogens exert specific effects on the fetus by epigenetic mechanisms.
While epigenetic effects may preserve the effect of a teratogen such as
diethylstilbestrol
Diethylstilbestrol (DES), also known as stilbestrol or stilboestrol, is a nonsteroidal estrogen medication, which is presently rarely used. In the past, it was widely used for a variety of indications, including pregnancy support for those with a ...
throughout the life of an affected child, the possibility of birth defects resulting from exposure of fathers or in second and succeeding generations of offspring has generally been rejected on theoretical grounds and for lack of evidence.
However, a range of male-mediated abnormalities have been demonstrated, and more are likely to exist.
FDA label information for Vidaza, a formulation of
5-azacitidine (an unmethylatable analog of cytidine that causes hypomethylation when incorporated into DNA) states that "men should be advised not to father a child" while using the drug, citing evidence in treated male mice of reduced fertility, increased
embryo loss
Embryo loss (also known as embryo death or embryo resorption) is the death of an embryo at any stage of its development which in humans, is between the second through eighth week after fertilization. Failed development of an embryo often results i ...
, and abnormal embryo development. In rats, endocrine differences were observed in offspring of males exposed to morphine.
In mice, second generation effects of diethylstilbesterol have been described occurring by epigenetic mechanisms.
Cancer subtypes
Skin cancer
Melanoma
Melanoma, also redundantly known as malignant melanoma, is a type of skin cancer that develops from the pigment-producing cells known as melanocytes. Melanomas typically occur in the skin, but may rarely occur in the mouth, intestines, or eye ( ...
is a deadly skin cancer that originates from melanocytes. Several epigenetic alterations are known to play a role in the transition of melanocytes to melanoma cells. This includes DNA methylation that can be inherited without making changes to the DNA sequence, as well as silencing the tumor suppressor genes in the epidermis that have been exposed to UV radiation for periods of time.
The silencing of tumor suppressor genes leads to
photocarcinogenesis which is associated to epigenetic alterations in DNA methylation, DNA methyltransferases, and histone acetylation.
These alterations are the consequence of deregulation of their corresponding enzymes. Several histone methyltransferases and demethylases are among these enzymes.
Prostate cancer
Prostate cancer
Prostate cancer is cancer of the prostate. Prostate cancer is the second most common cancerous tumor worldwide and is the fifth leading cause of cancer-related mortality among men. The prostate is a gland in the male reproductive system that sur ...
kills around 35,000 men yearly, and about 220,000 men are diagnosed with prostate cancer per year, in North America alone.
Prostate cancer is the second leading cause of cancer-caused fatalities in men, and within a man's lifetime, one in six men will have the disease.
Alterations in histone acetylation and DNA methylation occur in various genes influencing prostate cancer, and have been seen in genes involved in hormonal response.
More than 90% of prostate cancers show
gene silencing
Gene silencing is the regulation of gene expression in a cell to prevent the expression of a certain gene. Gene silencing can occur during either transcription or translation and is often used in research. In particular, methods used to silence ge ...
by
CpG island hypermethylation of the
GSTP1
Glutathione S-transferase P is an enzyme that in humans is encoded by the ''GSTP1'' gene.
Function
Glutathione S-transferases (GSTs) are a family of enzymes that play an important role in detoxification by catalyzing the conjugation of many hydr ...
gene
promoter, which protects
prostate
The prostate is both an Male accessory gland, accessory gland of the male reproductive system and a muscle-driven mechanical switch between urination and ejaculation. It is found only in some mammals. It differs between species anatomically, ...
cells from genomic damage that is caused by different oxidants or
carcinogen
A carcinogen is any substance, radionuclide, or radiation that promotes carcinogenesis (the formation of cancer). This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes. Several radioactive substan ...
s.
Real-time methylation-specific
polymerase chain reaction
The polymerase chain reaction (PCR) is a method widely used to rapidly make millions to billions of copies (complete or partial) of a specific DNA sample, allowing scientists to take a very small sample of DNA and amplify it (or a part of it) t ...
(PCR) suggests that many other genes are also hypermethylated.
Gene expression in the prostate may be modulated by nutrition and lifestyle changes.
Cervical cancer
The second most common malignant tumor in women is invasive
cervical cancer
Cervical cancer is a cancer arising from the cervix. It is due to the abnormal growth of cells that have the ability to invade or spread to other parts of the body. Early on, typically no symptoms are seen. Later symptoms may include abnormal ...
(ICC) and more than 50% of all
invasive cervical cancer (ICC) is caused by
oncongenic human papillomavirus
Human papillomavirus infection (HPV infection) is caused by a DNA virus from the ''Papillomaviridae'' family. Many HPV infections cause no symptoms and 90% resolve spontaneously within two years. In some cases, an HPV infection persists and res ...
16 (
HPV16
''Papillomaviridae'' is a family of non- enveloped DNA viruses whose members are known as papillomaviruses. Several hundred species of papillomaviruses, traditionally referred to as "types", have been identified infecting all carefully inspected ...
).
Furthermore,
cervix intraepithelial neoplasia (CIN) is primarily caused by oncogenic HPV16.
As in many cases, the causative factor for cancer does not always take a direct route from infection to the development of cancer. Genomic methylation patterns have been associated with invasive cervical cancer. Within the
HPV16L1 region, 14 tested CpG sites have significantly higher methylation in
CIN3+ than in HPV16 genomes of women without
CIN3.
Only 2/16 CpG sites tested in HPV16 upstream regulatory region were found to have association with increased methylation in CIN3+.
This suggests that the direct route from infection to cancer is sometimes detoured to a precancerous state in cervix intraepithelial neoplasia. Additionally, increased CpG site methylation was found in low levels in most of the five host nuclear genes studied, including 5/5
TERT
Telomerase reverse transcriptase (abbreviated to TERT, or hTERT in humans) is a catalytic subunit of the enzyme telomerase, which, together with the telomerase RNA component (TERC), comprises the most important unit of the telomerase complex.
T ...
, 1/4
DAPK1, 2/5
RARB,
MAL, and
CADM1
Cell adhesion molecule 1 is a protein that, in humans, is encoded by the ''CADM1'' gene.
Model organisms
Model organisms have been used in the study of CADM1 function. A conditional knockout mouse line, called ''Cadm1tm1.2Brd'' was generated. Ma ...
.
Furthermore, 1/3 of CpG sites in
mitochondrial DNA
Mitochondrial DNA (mtDNA or mDNA) is the DNA located in mitochondria, cellular organelles within eukaryotic cells that convert chemical energy from food into a form that cells can use, such as adenosine triphosphate (ATP). Mitochondrial D ...
were associated with increased methylation in CIN3+.
Thus, a correlation exists between CIN3+ and increased methylation of CpG sites in the HPV16 L1 open reading frame.
This could be a potential
biomarker
In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, ...
for future screens of cancerous and precancerous cervical disease.
Leukemia
Recent studies have shown that the
mixed-lineage leukemia (MLL) gene causes
leukemia
Leukemia ( also spelled leukaemia and pronounced ) is a group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or ' ...
by rearranging and fusing with other genes in different chromosomes, which is a process under epigenetic control.
Mutations in MLL block the correct regulatory regions in leukemia associated translocations or insertions causing malignant transformation controlled by HOX genes. This is what leads to the increase in white blood cells. Leukemia related genes are managed by the same pathways that control epigenetics, signaling transduction, transcriptional regulation, and energy metabolism. It was indicated that infections, electromagnetic fields and increased birth weight can contribute to being the causes of leukemia.
Sarcoma
There are about 15,000 new cases of sarcoma in the US each year, and about 6,200 people were projected to die of sarcoma in the US in 2014. Sarcomas comprise a large number of rare, histogenetically heterogeneous mesenchymal tumors that, for example, include chondrosarcoma, Ewing's sarcoma, leiomyosarcoma, liposarcoma, osteosarcoma, synovial sarcoma, and (alveolar and embryonal) rhabdomyosarcoma. Several oncogenes and tumor suppressor genes are epigenetically altered in sarcomas. These include APC, CDKN1A, CDKN2A, CDKN2B, Ezrin, FGFR1, GADD45A, MGMT, STK3, STK4, PTEN, RASSF1A, WIF1, as well as several miRNAs. Expression of epigenetic modifiers such as that of the BMI1 component of the PRC1 complex is deregulated in chondrosarcoma, Ewing's sarcoma, and osteosarcoma, and expression of the EZH2 component of the PRC2 complex is altered in Ewing's sarcoma and rhabdomyosarcoma. Similarly, expression of another epigenetic modifier, the LSD1 histone demethylase, is increased in chondrosarcoma, Ewing's sarcoma, osteosarcoma, and rhabdomyosarcoma. Drug targeting and inhibition of EZH2 in Ewing's sarcoma, or of LSD1 in several sarcomas, inhibits tumor cell growth in these sarcomas.
Identification methods
Previously, epigenetic profiles were limited to individual genes under scrutiny by a particular research team. Recently, however, scientists have been moving toward a more genomic approach to determine an entire genomic profile for cancerous versus healthy cells.
Popular approaches for measuring CpG methylation in cells include:
*
Bisulfite sequencing
Bisulfite sequencing (also known as bisulphite sequencing) is the use of bisulfite treatment of DNA before routine sequencing to determine the pattern of methylation. DNA methylation was the first discovered epigenetic mark, and remains the mo ...
*
Combined bisulfite restriction analysis (COBRA)
*
Methylation-specific PCR
*
MethyLight
*
Pyrosequencing
Pyrosequencing is a method of DNA sequencing (determining the order of nucleotides in DNA) based on the "sequencing by synthesis" principle, in which the sequencing is performed by detecting the nucleotide incorporated by a DNA polymerase. Pyrosequ ...
*
Restriction landmark genomic scanning Restriction landmark genomic scanning (RLGS) is a genome analysis method for rapid simultaneous visualization of thousands of landmarks, or restriction sites. Using a combination of restriction enzymes some of which are specific to DNA modification ...
*
Arbitrary primed PCR
*
HELP assay (HpaII tiny fragment enrichment by ligation-mediated PCR)
*
Chromatin immunoprecipitation Chromatin immunoprecipitation (ChIP) is a type of immunoprecipitation experimental technique used to investigate the interaction between proteins and DNA in the cell. It aims to determine whether specific proteins are associated with specific genom ...
ChIP-Chip using antibodies specific for methyl-CpG binding domain proteins
*
Methylated DNA immunoprecipitation
Methylated DNA immunoprecipitation (MeDIP or mDIP) is a large-scale (chromosome- or genome-wide) purification technique in molecular biology that is used to enrich for methylated DNA sequences. It consists of isolating methylated DNA fragments vi ...
Methyl-DIP
*Gene-expression profiles via
DNA microarray
A DNA microarray (also commonly known as DNA chip or biochip) is a collection of microscopic DNA spots attached to a solid surface. Scientists use DNA microarrays to measure the expression levels of large numbers of genes simultaneously or to ...
: comparing
mRNA
In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein.
mRNA is ...
levels from cancer cell lines before and after treatment with a demethylating agent
Since bisulfite sequencing is considered the gold standard for measuring CpG methylation, when one of the other methods is used, results are usually confirmed using bisulfite sequencing
Popular approaches for determining
histone modification
In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei. They act as spools around which DNA winds to create structural units called nucleosomes. Nucleosomes in turn ar ...
profiles in cancerous versus healthy cells include:
*
Mass spectrometry
Mass spectrometry (MS) is an analytical technique that is used to measure the mass-to-charge ratio of ions. The results are presented as a ''mass spectrum'', a plot of intensity as a function of the mass-to-charge ratio. Mass spectrometry is use ...
*Chromatin Immunoprecipitation Assay
Diagnosis and prognosis
Researchers are hoping to identify specific epigenetic profiles of various types and subtypes of cancer with the goal of using these profiles as tools to diagnose individuals more specifically and accurately.
Since epigenetic profiles change, scientists would like to use the different epigenomic profiles to determine the stage of development or level of aggressiveness of a particular cancer in patients. For example, hypermethylation of the genes coding for
Death-Associated Protein Kinase (DAPK), p16, and
Epithelial Membrane Protein 3 (EMP3) have been linked to more aggressive forms of
lung
The lungs are the primary organs of the respiratory system in humans and most other animals, including some snails and a small number of fish. In mammals and most other vertebrates, two lungs are located near the backbone on either side of t ...
,
colorectal
The large intestine, also known as the large bowel, is the last part of the gastrointestinal tract and of the digestive system in tetrapods. Water is absorbed here and the remaining waste material is stored in the rectum as feces before being ...
, and
brain cancer
A brain tumor occurs when abnormal cells form within the brain. There are two main types of tumors: malignant tumors and benign (non-cancerous) tumors. These can be further classified as primary tumors, which start within the brain, and secondar ...
s.
This type of knowledge can affect the way that doctors will diagnose and choose to treat their patients.
Another factor that will influence the treatment of patients is knowing how well they will respond to certain treatments. Personalized epigenomic profiles of cancerous cells can provide insight into this field. For example,
MGMT
MGMT () is an American indie rock band formed in 2002 in Middletown, Connecticut. It was founded by multi-instrumentalists Andrew VanWyngarden and Ben Goldwasser. Alongside VanWyngarden and Goldwasser, MGMT's live lineup currently consists of ...
is an enzyme that reverses the addition of
alkyl group
In organic chemistry, an alkyl group is an alkane missing one hydrogen.
The term ''alkyl'' is intentionally unspecific to include many possible substitutions.
An acyclic alkyl has the general formula of . A cycloalkyl is derived from a cycloalk ...
s to the nucleotide
guanine
Guanine () ( symbol G or Gua) is one of the four main nucleobases found in the nucleic acids DNA and RNA, the others being adenine, cytosine, and thymine (uracil in RNA). In DNA, guanine is paired with cytosine. The guanine nucleoside is called ...
.
Alkylating guanine, however, is the mechanism by which several
chemotherapeutic drugs act in order to disrupt DNA and cause
cell death
Cell death is the event of a biological cell ceasing to carry out its functions. This may be the result of the natural process of old cells dying and being replaced by new ones, as in programmed cell death, or may result from factors such as dis ...
.
Therefore, if the gene encoding MGMT in cancer cells is hypermethylated and in effect silenced or repressed, the chemotherapeutic drugs that act by methylating guanine will be more effective than in cancer cells that have a functional MGMT enzyme.
Epigenetic
biomarker
In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, ...
s can also be utilized as tools for molecular prognosis. In primary tumor and
mediastinal lymph node
A lymph node, or lymph gland, is a kidney-shaped organ of the lymphatic system and the adaptive immune system. A large number of lymph nodes are linked throughout the body by the lymphatic vessels. They are major sites of lymphocytes that inclu ...
biopsy
A biopsy is a medical test commonly performed by a surgeon, interventional radiologist, or an interventional cardiologist. The process involves extraction of sample cells or tissues for examination to determine the presence or extent of a diseas ...
samples, hypermethylation of both
CDKN2A
CDKN2A, also known as cyclin-dependent kinase inhibitor 2A, is a gene which in humans is located at chromosome 9, band p21.3. It is ubiquitously expressed in many tissues and cell types. The gene codes for two proteins, including the INK4 family ...
and
CDH13
T-cadherin, also known as cadherin 13, H-cadherin (heart), and CDH13, is a unique member of the cadherin superfamily of proteins because it lacks the transmembrane and cytoplasmic domains common to all other cadherins and is instead anchored to ...
serves as the marker for increased risk of faster cancer relapse and higher death rate of patients.
Treatment
![Decitabine](https://upload.wikimedia.org/wikipedia/commons/4/44/Decitabine.svg)
Epigenetic control of the proto-onco regions and the tumor suppressor sequences by conformational changes in histones plays a role in the formation and progression of cancer.
Pharmaceuticals that reverse epigenetic changes might have a role in a variety of cancers.
Recently, it is evidently known that associations between specific cancer histotypes and epigenetic changes can facilitate the development of novel epi-drugs. Drug development has focused mainly on modifying
DNA methyltransferase
In biochemistry, the DNA methyltransferase (DNA MTase, DNMT) family of enzymes catalyze the transfer of a methyl group to DNA. DNA methylation serves a wide variety of biological functions. All the known DNA methyltransferases use S-adenosyl m ...
,
histone acetyltransferase
Histone acetyltransferases (HATs) are enzymes that acetylate conserved lysine amino acids on histone proteins by transferring an acetyl group from acetyl-CoA to form ε-''N''-acetyllysine. DNA is wrapped around histones, and, by transferring an ...
(HAT) and
histone deacetylase (HDAC).
Drugs that specifically target the inverted methylation pattern of cancerous cells include the
DNA methyltransferase
In biochemistry, the DNA methyltransferase (DNA MTase, DNMT) family of enzymes catalyze the transfer of a methyl group to DNA. DNA methylation serves a wide variety of biological functions. All the known DNA methyltransferases use S-adenosyl m ...
inhibitors
azacitidine
Azacitidine, sold under the brand name Vidaza among others, is used for the treatment of myelodysplastic syndrome, myeloid leukemia, and juvenile myelomonocytic leukemia. It is a chemical analog of cytidine, a nucleoside in DNA and RNA. Azacit ...
and
decitabine
Decitabine, sold under the brand name Dacogen among others, acts as a nucleic acid synthesis inhibitor. It is a medication for the treatment of myelodysplastic syndromes, a class of conditions where certain blood cells are dysfunctional, and for ...
.
These hypomethylating agents are used to treat
myelodysplastic syndrome
A myelodysplastic syndrome (MDS) is one of a group of cancers in which immature blood cells in the bone marrow do not mature, and as a result, do not develop into healthy blood cells. Early on, no symptoms typically are seen. Later, symptoms may ...
,
a
blood cancer
Tumors of the hematopoietic and lymphoid tissues (American English) or tumours of the haematopoietic and lymphoid tissues (British English) are tumors that affect the blood, bone marrow, lymph, and lymphatic system. Because these tissues are all ...
produced by abnormal
bone marrow stem cells.
These agents inhibit all three types of active DNA methyltransferases, and had been thought to be highly toxic, but proved to be effective when used in low dosage, reducing progression of myelodysplastic syndrome to
leukemia
Leukemia ( also spelled leukaemia and pronounced ) is a group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or ' ...
.
Histone deacetylase (HDAC) inhibitors show efficacy in treatment of
T cell lymphoma
T-cell lymphoma is a rare form of cancerous lymphoma affecting T-cells. Lymphoma arises mainly from the uncontrolled proliferation of T-cells and can become cancerous.
T-cell lymphoma is categorized under Non-Hodgkin lymphoma (NHL) and represents ...
. two HDAC inhibitors,
vorinostat
Vorinostat (rINN) also known as Suberoylanilide hydroxamic acid ( suberoyl+anilide+ hydroxamic acid abbreviated as SAHA) is a member of a larger class of compounds that inhibit histone deacetylases (HDAC). Histone deacetylase inhibitors (HDI) ...
and
romidepsin
Romidepsin, also known as Istodax, is an anticancer agent used in cutaneous T-cell lymphoma (CTCL) and other peripheral T-cell lymphomas (PTCLs). Romidepsin is a natural product obtained from the bacterium ''Chromobacterium violaceum'', and wo ...
, have been approved by the
Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
.
However, since these HDAC inhibitors alter the
acetylation
:
In organic chemistry, acetylation is an organic esterification reaction with acetic acid. It introduces an acetyl group into a chemical compound. Such compounds are termed ''acetate esters'' or simply '' acetates''. Deacetylation is the oppo ...
state of many proteins in addition to the histone of interest, knowledge of the underlying mechanism at the molecular level of patient response is required to enhance the efficiency of using such inhibitors as treatment.
Treatment with HDAC inhibitors has been found to promote
gene reactivation after DNA methyl-transferases inhibitors have repressed transcription.
Panobinostat
Panobinostat, sold under the brand name Farydak, is a medication used for the treatment of multiple myeloma. It is a hydroxamic acid and acts as a non-selective histone deacetylase inhibitor (pan-HDAC inhibitor).[myeloma
Multiple myeloma (MM), also known as plasma cell myeloma and simply myeloma, is a cancer of plasma cells, a type of white blood cell that normally produces antibodies. Often, no symptoms are noticed initially. As it progresses, bone pain, anemi ...]
.
Other pharmaceutical targets in research are
histone lysine methyltransferases (KMT) and protein arginine methyltransferases (PRMT).
Preclinical study has suggested that
lunasin may have potentially beneficial epigenetic effects.
Epigenetic Therapy
Epigenetic therapy of cancer has shown to be a promising and possible treatment of cancerous cells. Epigenetic inactivation is an ideal target for cancerous cells because it targets genes imperative for controlling cell growth, specifically cancer cell growth. It is crucial for these genes to be reactivated in order to suppress tumor growth and sensitize the cells to cancer curing therapies. Typical chemotherapy aims to kill and eliminate cancer cells in the body. Cancer initiated by genetic alterations of cells are typically permanent and nearly impossible to reverse, this differs from epigenetic cancer because the cancer causing epigenetic aberrations have the capability of being reversed, and the cells being returned to normal function. The ability for epigenetic mechanisms to be reversed is attributed to the fact that the coding of the genes being silenced through histone and DNA modification is not being altered.
There are two primary types of epigenetic alterations in cancer cells, these are known as DNA methylation and Histone modification. It is the goal of epigenetic therapies to inhibit these alterations. DNA Methyltransferases (DNMTs) and Histone Deacetylases (HDAC) are the primary catalyzes of the epigenetic modifications of cancer cells. The goal for epigenetic therapies is to repress this methylation and reverse these modifications in order to create a new epigenome where cancer cells no longer thrive and tumor suppression is the new function. Synthetic drugs are used as tools in epigenetic therapies due to their ability to inhibit enzymes causing histone modifications and DNA methylations. Combination therapy is one method of epigenetic therapy which involves the use of more than one synthetic drug, these drugs include a low dose DNMT inhibitor as well as an HDAC inhibitor. Together, these drugs are able to target the linkage between DNA methylation and Histone modification.
The goal of epigenetic therapies for cancer in relation to DNA methylation is to both decrease the methylation of DNA and in turn decrease the silencing of genes related to tumor suppression.
The term associated with decreasing the methylation of DNA will be known as hypomethylation. The Food and Drug Administration (FDA) has currently approved one hypomethylating agent which, through the conduction of clinical trials, has shown promising results when utilized to treat patients with Myelodysplastic Syndrome (MDS).
This hypomethylating agent is known as the doozy analogue of 5-azacytidine and works to promote hypomethylation by targeting all DNA methyltransferases for degradation.
See also
*
Pharmacoepigenetics
*
Regulation of transcription in cancer Generally, in progression to cancer, hundreds of genes are silenced or activated. Although silencing of some genes in cancers occurs by mutation, a large proportion of carcinogenic gene silencing is a result of altered DNA methylation (see DNA meth ...
References
{{Portal bar, Biology, Medicine
Epigenetics