Histone deacetylase 6 is an
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 ...
that in humans is encoded by the ''HDAC6''
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
.
HDAC6 has emerged as a highly promising candidate to selectively inhibit as a therapeutic strategy to combat several types of cancer and neurodegenerative disorders.
Function
Histones play a critical role in transcriptional regulation, cell cycle progression, and developmental events. Histone acetylation/deacetylation alters chromatin structure and affects transcription. The protein encoded by this gene belongs to class II of the histone deacetylase/acuc/apha family. It contains an internal duplication of two catalytic domains that appear to function independently of each other. This protein possesses histone deacetylase activity and represses transcription.
It retracts the
cilium
The cilium, plural cilia (), is a membrane-bound organelle found on most types of eukaryotic cell, and certain microorganisms known as ciliates. Cilia are absent in bacteria and archaea. The cilium has the shape of a slender threadlike projecti ...
of the cell, which is necessary prior to
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 ...
.
[*]
HDAC encourages
cell motility
Motility is the ability of an organism to move independently, using metabolic energy.
Definitions
Motility, the ability of an organism to move independently, using metabolic energy, can be contrasted with sessility, the state of organisms th ...
and catalyzes
α-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 ...
deacetylation
:
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 opposit ...
.
As a result the enzyme encourages cancer cell metastasis.
HDAC6 affects transcription and translation by regulating
heat-shock protein 90 (Hsp90).
HDAC6 is required in the formation of
stress granule
Stress granules are dense aggregations in the cytosol composed of proteins and RNAs that appear when the cell is under stress. The RNA molecules stored are stalled translation pre-initiation complexes: failed attempts to make protein from mRNA. St ...
(SG) proteins and is instrumental in SG formation; pharmacological inhibition or genetic removal of HDAC6 abolished SG formation.
HDAC6 bonds with high affinity to
ubiquitinated
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. Fou ...
proteins.
HDAC6 is involved in
leptin
Leptin (from Ancient Greek, Greek λεπτός ''leptos'', "thin" or "light" or "small") is a hormone predominantly made by adipose cells and enterocytes in the small intestine that helps to regulate Energy homeostasis, energy balance by inhib ...
sensitivity.
HDAC6 deacetylates
tyrosine
-Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a non-essential amino acid with a polar side group. The word "tyrosine" is from the Gr ...
residue T178 on
TAK1.
Clinical relevance
Mutations in this gene have been associated to
Alzheimer's disease
Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...
.
Over expression of this protein correlates 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 ...
and cell survival. HDAC6 also encourages
metastasis
Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then, ...
of cancer cells.
Since HDAC6 is dysregulated and/or implicated in several cancers and neurodegenerative disorders, pharmacological inhibition of this specific enzyme holds great therapeutic potential and could also limit side effects associated with pan-inhibitors of multiple HDAC enzymes. Selective inhibition of HDAC6 as a strategy to treat cancers is however also subject of debate, since some HDAC6 inhibitors exhibited anti-tumor activity ''in vitro'' and ''in vivo'' only when administered in high concentrations, which also produced off-target effects. The findings suggest that further study is needed to clarify data on anti-cancer effects of selective HDAC6 inhibitors.
Interactions
HDAC6 has been shown to
interact
Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...
with
HDAC11
Histone deacetylase 11 is a 39kDa histone deacetylase enzyme that in humans is encoded by the ''HDAC11'' gene on chromosome 3 in humans and chromosome 6 in mice.
It is the only Class IV HDAC since it is not highly homologous with either Rpd3 or hd ...
and
Zinc finger and BTB domain-containing protein 16
Zinc finger and BTB domain-containing protein 16 is a protein that in humans is encoded by the ''ZBTB16'' gene.
Function
This gene is a member of the Krueppel C2H2-type zinc-finger protein family and encodes a zinc finger transcription factor ...
.
HDAC6 interacts with SG (
Stress granule
Stress granules are dense aggregations in the cytosol composed of proteins and RNAs that appear when the cell is under stress. The RNA molecules stored are stalled translation pre-initiation complexes: failed attempts to make protein from mRNA. St ...
) protein
G3BP1
Ras GTPase-activating protein-binding protein 1 is an enzyme that in humans is encoded by the ''G3BP1'' gene.
This gene encodes one of the DNA-unwinding enzymes which prefers partially unwound 3'-tailed substrates and can also unwind partial RNA/ ...
.
See also
*
Histone deacetylase
Histone deacetylases (, HDAC) are a class of enzymes that remove acetyl groups (O=C-CH3) from an ε-N-acetyl lysine amino acid on a histone, allowing the histones to wrap the DNA more tightly. This is important because DNA is wrapped around his ...
References
Further reading
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External links
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