Histone deacetylases (, HDAC) are a class of
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
s that remove
acetyl group
In organic chemistry, acetyl is a functional group with the chemical formula and the structure . It is sometimes represented by the symbol Ac (not to be confused with the element actinium). In IUPAC nomenclature, acetyl is called ethanoyl, ...
s (O=C-CH
3) from an ε-N-acetyl
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 ...
amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
on a
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 ...
, allowing the histones to wrap the DNA more tightly.
This is important because
DNA is wrapped around histones, and DNA expression is regulated by acetylation and de-acetylation. Its action is opposite to that of
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 ...
. HDAC proteins are now also called lysine deacetylases (KDAC), to describe their function rather than their target, which also includes non-histone proteins.
HDAC super family
Together with the
acetylpolyamine amidohydrolases and the
acetoin utilization protein
Acetoin, also known as 3-hydroxybutanone or acetyl methyl carbinol, is an organic compound with the formula CH3CH(OH)C(O)CH3. It is a colorless liquid with a pleasant, buttery odor. It is chiral. The form produced by bacteria is (''R'')-acetoin. ...
s, the histone deacetylases form an ancient protein superfamily known as the histone deacetylase superfamily.
Classes of HDACs in higher eukaryotes
HDACs, are classified in four classes depending on sequence homology to the yeast original enzymes and domain organization:
HDAC (except class III) contain zinc and are known as Zn
2+-dependent histone deacetylases.
They feature a classical arginase fold and are structurally and mechanistically distinct from
sirtuin
Sirtuins are a family of signaling proteins involved in metabolic regulation. They are ancient in animal evolution and appear to possess a highly conserved structure throughout all kingdoms of life. Chemically, sirtuins are a class of proteins t ...
s (class III), which fold into a
Rossmann architecture and are
NAD+ dependent.
Subtypes
HDAC proteins are grouped into four classes (see above) based on function and DNA sequence similarity. Class I, II and IV are considered "classical" HDACs whose activities are inhibited by
trichostatin A
Trichostatin A (TSA) is an organic compound that serves as an antifungal antibiotic and selectively inhibits the class I and II mammalian histone deacetylase (HDAC) families of enzymes, but not class III HDACs (i.e., sirtuins). However, there are ...
(TSA) and have a zinc dependent active site, whereas Class III enzymes are a family of NAD
+-dependent proteins known as
sirtuin
Sirtuins are a family of signaling proteins involved in metabolic regulation. They are ancient in animal evolution and appear to possess a highly conserved structure throughout all kingdoms of life. Chemically, sirtuins are a class of proteins t ...
s and are not affected by TSA. Homologues to these three groups are found in yeast having the names: reduced potassium dependency 3 (Rpd3), which corresponds to Class I; histone deacetylase 1 (hda1), corresponding to Class II; and silent information regulator 2 (
Sir2
Sirtuin 1, also known as nicotinamide adenine dinucleotide, 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 (''Sacchar ...
), corresponding to Class III. Class IV contains just one isoform (HDAC11), which is not highly homologous with either Rpd3 or hda1 yeast enzymes, and therefore HDAC11 is assigned to its own class. The Class III enzymes are considered a separate type of enzyme and have a different mechanism of action; these enzymes are NAD
+-dependent, whereas HDACs in other classes require Zn
2+ as a cofactor.
Evolution
HDACs are conserved across evolution, showing orthologs in all eukaryotes and even in
Archaea
Archaea ( ; singular archaeon ) is a domain of single-celled organisms. These microorganisms lack cell nuclei and are therefore prokaryotes. Archaea were initially classified as bacteria, receiving the name archaebacteria (in the Archaebac ...
. All upper eukaryotes, including vertebrates, plants and arthropods, possess at least one HDAC per class, while most vertebrates carry the 11 canonical HDACs, with the exception of bone fish, which lack HDAC2 but appears to have an extra copy of HDAC11, dubbed HDAC12. Plants carry additional HDACs compared to animals, putatively to carry out the more complex transcriptional regulation required by these sessile organisms. HDACs appear to be deriving from an ancestral acetyl-binding domain, as HDAC homologs have been found in bacteria in the form of Acetoin utilization proteins (AcuC) proteins.
Subcellular distribution
Within the Class I HDACs, HDAC 1, 2, and 3 are found primarily in the nucleus, whereas HDAC8 is found in both the nucleus and the cytoplasm, and is also membrane-associated. Class II HDACs (HDAC4, 5, 6, 7 9, and 10) are able to shuttle in and out of the nucleus, depending on different signals.
HDAC6 is a cytoplasmic, microtubule-associated enzyme. HDAC6 deacetylates
tubulin
Tubulin in molecular biology can refer either to the tubulin protein superfamily of globular proteins, or one of the member proteins of that superfamily. α- and β-tubulins polymerize into microtubules, a major component of the eukaryotic cytoske ...
,
Hsp90
Hsp90 (heat shock protein 90) is a chaperone protein that assists other proteins to fold properly, stabilizes proteins against heat stress, and aids in protein degradation. It also stabilizes a number of proteins required for tumor growth, ...
, and
cortactin
Cortactin (from "''cortical actin'' binding protein") is a monomeric protein located in the cytoplasm of cells that can be activated by external stimuli to promote polymerization and rearrangement of the actin cytoskeleton, especially the actin cor ...
, and forms complexes with other partner proteins, and is, therefore, involved in a variety of biological processes.
Function
Histone modification
Histone tails are normally positively charged due to
amine
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 substituen ...
groups present on their
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 ...
and
arginine
Arginine is the amino acid with the formula (H2N)(HN)CN(H)(CH2)3CH(NH2)CO2H. The molecule features a guanidino group appended to a standard amino acid framework. At physiological pH, the carboxylic acid is deprotonated (−CO2−) and both the am ...
amino acids. These positive charges help the histone tails to interact with and bind to the negatively charged
phosphate group
In chemistry, a phosphate is an anion, salt, functional group or ester derived from a phosphoric acid. It most commonly means orthophosphate, a derivative of orthophosphoric acid .
The phosphate or orthophosphate ion is derived from phosphor ...
s on the DNA backbone.
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 ...
, which occurs normally in a cell, neutralizes the positive charges on the histone by changing amines into
amide
In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a compound with the general formula , where R, R', and R″ represent organic groups or hydrogen atoms. The amide group is called a peptide bond when it is ...
s and decreases the ability of the histones to bind to DNA. This decreased binding allows
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 ...
expansion, permitting genetic
transcription
Transcription refers to the process of converting sounds (voice, music etc.) into letters or musical notes, or producing a copy of something in another medium, including:
Genetics
* Transcription (biology), the copying of DNA into RNA, the fir ...
to take place. Histone deacetylases remove those acetyl groups, increasing the positive charge of histone tails and encouraging high-affinity binding between the histones and DNA backbone. The increased DNA binding condenses DNA structure, preventing transcription.
Histone deacetylase is involved in a series of pathways within the living system. According to the ''Kyoto Encyclopedia of Genes and Genomes'' (
KEGG
KEGG (Kyoto Encyclopedia of Genes and Genomes) is a collection of databases dealing with genomes, biological pathways, diseases, drugs, and chemical substances. KEGG is utilized for bioinformatics research and education, including data analysis i ...
), these are:
* Environmental information processing;
signal transduction
Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellula ...
;
notch signaling pathway
The Notch signaling pathway is a highly Conserved sequence, conserved cell signaling system present in most animals. Mammals possess four different Notch proteins, notch receptors, referred to as NOTCH1, NOTCH2, Notch 3, NOTCH3, and NOTCH4. The ...
br>
PATH:ko04330* Cellular processes; cell growth and death;
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 ...
br>
PATH:ko04110* Human diseases; cancers;
chronic myeloid leukemia
Chronic myelogenous leukemia (CML), also known as chronic myeloid leukemia, is a cancer of the white blood cells. It is a form of leukemia characterized by the increased and unregulated growth of myeloid cells in the bone marrow and the accumulat ...
br>
PATH:ko05220
Histone acetylation plays an important role in the regulation of gene expression. Hyperacetylated chromatin is transcriptionally active, and hypoacetylated chromatin is silent. A study on mice found that a specific subset of mouse genes (7%) was deregulated in the absence of HDAC1.
Their study also found a regulatory
crosstalk
In electronics, crosstalk is any phenomenon by which a signal transmitted on one circuit or channel of a transmission system creates an undesired effect in another circuit or channel. Crosstalk is usually caused by undesired capacitive, induc ...
between
HDAC1
Histone deacetylase 1 (HDAC1) is an enzyme that in humans is encoded by the ''HDAC1'' gene.
Function
Histone acetylation and deacetylation, catalyzed by multisubunit complexes, play a key role in the regulation of eukaryotic gene expression. T ...
and
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 ...
and suggest a novel function for HDAC1 as a transcriptional coactivator. HDAC1 expression was found to be increased in the prefrontal cortex of schizophrenia subjects,
negatively correlating with the expression of
GAD67
Glutamate decarboxylase or glutamic acid decarboxylase (GAD) is an enzyme that catalyzes the decarboxylation of glutamate to gamma-aminobutyric acid (GABA) and carbon dioxide (). GAD uses pyridoxal-phosphate (PLP) as a cofactor. The reaction p ...
mRNA.
Histone modification in neurons
Neuron
A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. N ...
s are electrically excitable cells within the
nervous system
In biology, the nervous system is the highly complex part of an animal that coordinates its actions and sensory information by transmitting signals to and from different parts of its body. The nervous system detects environmental changes th ...
and are organized together in
circuits.
In
hippocampal
The hippocampus (via Latin from Greek , 'seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic system, an ...
neurons in culture, when spontaneous electrical activity occurred it was sufficient to cause
nuclear export
A nuclear export signal (NES) is a short target peptide containing 4 hydrophobic residues in a protein that targets it for export from the cell nucleus to the cytoplasm through the nuclear pore complex using nuclear transport. It has the opposite ...
of the histone deacetylase HDAC4. Another histone deacetylase, HDAC5, was translocated to the
cytoplasm
In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. The ...
after stimulation of calcium flux through synaptic
NMDA receptor
The ''N''-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other two being AMPA rece ...
s.
Of 4,407
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
s found in the
nuclei of rat
forebrain
In the anatomy of the brain of vertebrates, the forebrain or prosencephalon is the Anatomical terms of location#Directional terms, rostral (forward-most) portion of the brain. The forebrain (prosencephalon), the midbrain (mesencephalon), and hin ...
neurons in culture, after activation of the neurons, 2,860 changed in nuclear concentration due to nucleocytoplasmic shuttling or
sythesis or
degradation
Degradation may refer to:
Science
* Degradation (geology), lowering of a fluvial surface by erosion
* Degradation (telecommunications), of an electronic signal
* Biodegradation of organic substances by living organisms
* Environmental degradation ...
of the proteins.
After neuronal stimulation, of all proteins, HDAC4 had the largest concentration decrease, due to shuttling out of the nucleus.
A decrease in a HDAC would cause greater presence of
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 ...
on histone tails. Histone acetylation is associated with active transcription of genes,
(see top figure in this section) and decrease in a histone deacetylase would have
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 ...
effects by likely maintaining or increasing gene
transcriptions. The large decrease in HDAC4 after neuron activation may have a similarly large effect on neuronal function.
Non-histone effects
It is a mistake to regard HDACs solely in the context of regulating gene transcription by modifying histones and chromatin structure, although that appears to be the predominant function. The function, activity, and stability of proteins can be controlled by
post-translational modification
Post-translational modification (PTM) is the covalent and generally enzymatic modification of proteins following protein biosynthesis. This process occurs in the endoplasmic reticulum and the golgi apparatus. Proteins are synthesized by ribosome ...
s. Protein
phosphorylation
In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...
is perhaps the most widely studied and understood modification in which certain amino acid residues are phosphorylated by the action of
protein kinase
A protein kinase is a kinase which selectively modifies other proteins by covalently adding phosphates to them (phosphorylation) as opposed to kinases which modify lipids, carbohydrates, or other molecules. Phosphorylation usually results in a fu ...
s or dephosphorylated by the action of
phosphatases
In biochemistry, a phosphatase is an enzyme that uses water to cleave a phosphoric acid monoester into a phosphate ion and an alcohol. Because a phosphatase enzyme catalyzes the hydrolysis of its substrate, it is a subcategory of hydrolases. ...
. 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 ...
of lysine residues is emerging as an analogous mechanism, in which non-histone proteins are acted on by acetylases and deacetylases.
It is in this context that HDACs are being found to interact with a variety of non-histone proteins—some of these are
transcription factor
In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fu ...
s and
co-regulators, some are not. Note the following four examples:
*
HDAC6
Histone deacetylase 6 is an enzyme that in humans is encoded by the ''HDAC6'' gene. HDAC6 has emerged as a highly promising candidate to selectively inhibit as a therapeutic strategy to combat several types of cancer and neurodegenerative disorder ...
is associated with
aggresomes In eukaryotic cells, an aggresome refers to an aggregation of misfolded proteins in the cell, formed when the protein degradation system of the cell is overwhelmed. Aggresome formation is a highly regulated process that possibly serves to organize m ...
. Misfolded protein aggregates are tagged by
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 ...
ation and removed from the cytoplasm by
dynein
Dyneins are a family of cytoskeletal motor proteins that move along microtubules in cells. They convert the chemical energy stored in ATP to mechanical work. Dynein transports various cellular cargos, provides forces and displacements importa ...
motors via the microtubule network to an organelle termed the aggresome. HDAC 6 binds polyubiquitinated misfolded proteins and links to dynein motors, thereby allowing the misfolded protein cargo to be physically transported to chaperones and proteasomes for subsequent destruction.
HDAC6 is important regulator of HSP90 function and its inhibitor proposed to treat metabolic disorders.
*
PTEN is an important phosphatase involved in cell signaling via
phosphoinositol
Inositol phosphates are a group of mono- to hexaphosphorylated inositols. They play crucial roles in diverse cellular functions, such as cell growth, apoptosis, cell migration, endocytosis, and cell differentiation.
The group comprises:
* inositol ...
s and the
AKT
Protein kinase B (PKB), also known as Akt, is the collective name of a set of three serine/threonine-specific protein kinases that play key roles in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, tran ...
/
PI3 kinase
Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which i ...
pathway. PTEN is subject to complex regulatory control via phosphorylation, ubiquitination, oxidation and acetylation. Acetylation of PTEN by the histone acetyltransferase p300/CBP-associated factor (
PCAF
P300/CBP-associated factor (PCAF), also known as K(lysine) acetyltransferase 2B (KAT2B), is a human gene and transcriptional coactivator associated with p53.
Structure
Several domains of PCAF can act independently or in unison to enable its funct ...
) can repress its activity; on the converse, deacetylation of PTEN by
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 ...
deacetylase and, by
HDAC1
Histone deacetylase 1 (HDAC1) is an enzyme that in humans is encoded by the ''HDAC1'' gene.
Function
Histone acetylation and deacetylation, catalyzed by multisubunit complexes, play a key role in the regulation of eukaryotic gene expression. T ...
, can stimulate its activity.
* APE1/Ref-1 (
APEX1) is a multifunctional protein possessing both DNA repair activity (on abasic and single-strand break sites) and transcriptional regulatory activity associated with
oxidative stress
Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily Detoxification, detoxify the reactive intermediates or to repair the resulting damage. Disturbances ...
. APE1/Ref-1 is acetylated by PCAF; on the converse, it is stably associated with and deacetylated by Class I HDACs. The acetylation state of APE1/Ref-1 does not appear to affect its
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 ...
activity, but it does regulate its transcriptional activity such as its ability to bind to the PTH promoter and initiate transcription of the
parathyroid hormone
Parathyroid hormone (PTH), also called parathormone or parathyrin, is a peptide hormone secreted by the parathyroid glands that regulates the serum calcium concentration through its effects on bone, kidney, and intestine.
PTH influences bone re ...
gene.
*
NF-κB
Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a protein complex that controls transcription of DNA, cytokine production and cell survival. NF-κB is found in almost all animal cell types and is involved in cellular ...
is a key transcription factor and effector molecule involved in responses to cell stress, consisting of a p50/p65 heterodimer. The p65 subunit is controlled by acetylation via PCAF and by deacetylation via
HDAC3
Histone deacetylase 3 is an enzyme encoded by the ''HDAC3'' gene in both humans and mice.
Function
Histones are highly alkaline proteins that package and order DNA into structural units called nucleosomes, which comprise the major protein comp ...
and HDAC6.
These are just some examples of constantly emerging non-histone, non-chromatin roles for HDACs.
Neurodegenerative diseases
Inherited mutations in the gene encoding
FUS, an
RNA
Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...
/
DNA binding protein, are causally linked to
amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) or Lou Gehrig's disease, is a neurodegenerative disease that results in the progressive loss of motor neurons that control voluntary muscles. ALS is the most comm ...
(ALS).
FUS has a pivotal role in the
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 ...
response involving its direct interaction with histone deacetylase 1 (HDAC1). ALS mutant FUS proteins are defective in the DNA damage response and in
recombinational 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 also show reduced interaction with HDAC1.
Ataxia-telangiectasia is due to mutation in the
''Atm'' gene. Wild-type ''Atm'' encodes a protein kinase employed in
chromatin remodeling
Chromatin remodeling is the dynamic modification of chromatin architecture to allow access of condensed genomic DNA to the regulatory transcription machinery proteins, and thereby control gene expression. Such remodeling is principally carried out ...
and in
epigenetic alterations that are required for
repairing DNA double-strand breaks.
''Atm'' mutation causes
neuron
A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. N ...
s to accumulate nuclear histone deacetylase 4 (HDAC4) resulting in increased histone deacetylation and altered neuronal gene expression that likely contributes to the
neurodegeneration
A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic ...
characteristic of ataxia-telangiectasia.
HDAC inhibitors
Histone deacetylase inhibitors (HDIs) have a long history of use in psychiatry and neurology as mood stabilizers and anti-epileptics, for example,
valproic acid
Valproate (VPA) and its valproic acid, sodium valproate, and valproate semisodium forms are medications primarily used to treat epilepsy and bipolar disorder and prevent migraine headaches. They are useful for the prevention of seizures in those ...
. In more recent times, HDIs are being studied as a mitigator or treatment for
neurodegenerative diseases
A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic ...
.
Also in recent years, there has been an effort to develop HDIs for cancer therapy.
Vorinostat (SAHA) was
FDA
The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...
approved in 2006 for the treatment of cutaneous manifestations in patients with
cutaneous T cell lymphoma
Cutaneous T-cell lymphoma (CTCL) is a class of non-Hodgkin lymphoma, which is a type of cancer of the immune system. Unlike most non-Hodgkin lymphomas (which are generally B-cell-related), CTCL is caused by a mutation of T cells. The cancerous T ...
(CTCL) that have failed previous treatments. A second HDI, Istodax (
romidepsin
Romidepsin, also known as Istodax, is an antineoplastic, 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 viola ...
), was approved in 2009 for patients with CTCL. The exact mechanisms by which the compounds may work are unclear, but
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 ...
pathways are proposed.
In addition, a clinical trial is studying valproic acid effects on the latent pools of HIV in infected persons. HDIs are currently being investigated as chemosensitizers for cytotoxic chemotherapy or radiation therapy, or in association with DNA methylation inhibitors based on in vitro synergy.
Isoform selective HDIs which can aid in elucidating role of individual HDAC isoforms have been developed.
HDAC inhibitors have effects on non-histone proteins that are related to acetylation. HDIs can alter the degree of acetylation of these molecules and, therefore, increase or repress their activity. For the four examples given above (see ''Function'') on HDACs acting on non-histone proteins, in each of those instances the HDAC inhibitor
Trichostatin A (TSA) blocks the effect. HDIs have been shown to alter the activity of many transcription factors, including
ACTR,
cMyb, E2F1,
EKLF
Krueppel-like factor 1 is a protein that in humans is encoded by the KLF1 gene. The gene for KLF1 is on the human chromosome 19 and on mouse chromosome 8. Krueppel-like factor 1 is a transcription factor that is necessary for the proper maturatio ...
,
FEN 1, GATA,
HNF-4, HSP90,
Ku70
Ku70 is a protein that, in humans, is encoded by the ''XRCC6'' gene.
Function
Together, Ku70 and Ku80 make up the Ku heterodimer, which binds to DNA double-strand break ends and is required for the non-homologous end joining (NHEJ) pathway of ...
, NFκB,
PCNA
Proliferating cell nuclear antigen (PCNA) is a DNA clamp that acts as a processivity factor for DNA polymerase δ in eukaryotic cells and is essential for replication. PCNA is a homotrimer and achieves its processivity by encircling the DNA, whe ...
, p53,
RB, Runx, SF1 Sp3, STAT,
TFIIE
Transcription factor II E (TFIIE) is one of several general transcription factors that make up the RNA polymerase II preinitiation complex. It is a tetramer of two alpha and two beta chains and interacts with TAF6/TAFII80, ATF7IP, and varicella ...
,
TCF, YY1.
The
ketone body
Ketone bodies are water-soluble molecules that contain the ketone groups produced from fatty acids by the liver (ketogenesis). Ketone bodies are readily transported into tissues outside the liver, where they are converted into acetyl-CoA (acetyl ...
β-hydroxybutyrate
β-Hydroxybutyric acid, also known as 3-hydroxybutyric acid or BHB, is an organic compound and a beta hydroxy acid with the chemical formula CH3CH(OH)CH2CO2H; its conjugate base is β-hydroxybutyrate, also known as 3-hydroxybutyrate. β-Hydroxyb ...
has been shown in mice to increase
gene expression
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. The ...
of FOXO3a by histone deacetylase inhibition.
Histone deacetylase inhibitors may modulate the latency of some viruses, resulting in reactivation. This has been shown to occur, for instance, with a latent ''
human herpesvirus-6
Human herpesvirus 6 (HHV-6) is the common collective name for ''human betaherpesvirus 6A'' (HHV-6A) and ''human betaherpesvirus 6B'' (HHV-6B). These closely related viruses are two of the nine known human herpesviruses, herpesviruses that have hu ...
'' infection.
Histone deacetylase inhibitors have shown activity against certain ''Plasmodium'' species and stages which may indicate they have potential in malaria treatment. It has been shown that HDIs accumulate acetylated histone H3K9/H3K14, a downstream target of class I HDACs.
See also
*
Histone acetyltransferase (HAT)
*
Histone deacetylase inhibitor
Histone deacetylase inhibitors (HDAC inhibitors, HDACi, HDIs) are chemical compounds that inhibit histone deacetylases.
HDIs have a long history of use in psychiatry and neurology as mood stabilizers and anti-epileptics. More recently they are bei ...
*
Histone methyltransferase (HMT)
*
Histone-modifying enzymes
Histone-modifying enzymes are enzymes involved in the modification of histone substrates after protein translation and affect cellular processes including gene expression. To safely store the eukaryotic genome, DNA is wrapped around four core hi ...
*
RNA polymerase control by chromatin structure
RNA polymerase II (RNAP II and Pol II) is a multiprotein complex that transcribes DNA into precursors of messenger RNA (mRNA) and most small nuclear RNA (snRNA) and microRNA. It is one of the three RNAP enzymes found in the nucleus of eukaryotic ...
References
External links
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Animationat
Merck
Merck refers primarily to the German Merck family and three companies founded by the family, including:
* the Merck Group, a German chemical, pharmaceutical and life sciences company founded in 1668
** Merck Serono (known as EMD Serono in the Unite ...
{{DEFAULTSORT:Histone Deacetylase
EC 3.5.1