Histone deacetylases are a class of enzymes that remove acetyl groups 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 histones,
and DNA expression is regulated by acetylation and de-acetylation. Its
action is opposite to that of histone acetyltransferase. HDAC proteins are now
also called lysine deacetylases, 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 proteins, 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 contain zinc and are known as Zn-dependent histone deacetylases.
Subtypes HDAC proteins are grouped into four
classes based on function and DNA sequence similarity. Class I, II and IV
are considered "classical" HDACs whose activities are inhibited by trichostatin
A and have a zinc dependent active site, whereas Class III enzymes are a family
of NAD+-dependent proteins known as sirtuins and are not affected by TSA.
Homologues to these three groups are found in yeast having the names: reduced
potassium dependency 3, which corresponds to Class I; histone
deacetylase 1, corresponding to Class II; and silent information regulator 2,
corresponding to Class III. Class IV contains just one isoform, 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 Zn2+ as a cofactor.
Subcellular distribution Within the Class I HDACs, HDAC 1, 2, and
8 are found primarily in the nucleus, whereas HDAC3 is found in both the
nucleus and the cytoplasm, and is also membrane-associated. Class II HDACs are
able to shuttle in and out of the nucleus, depending on different signals.
HDAC6 is a cytoplasmic, microtuble-associated enzyme. HDAC6
deacetylates tubulin, Hsp90, and cortactin, 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 groups present on their lysine and arginine amino acids.
These positive charges help the histone tails to interact with and bind to the
negatively charged phosphate groups on the DNA backbone. Acetylation, which
occurs normally in a cell, neutralizes the positive charges on the histone by
changing amines into amides and decreases the ability of the histones to
bind to DNA. This decreased binding allows chromatin expansion, permitting
genetic transcription 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, these
are: Environmental information processing;
signal transduction; notch signaling pathway PATH:ko04330
Cellular processes; cell growth and death; cell cycle PATH:ko04110
Human diseases; cancers; chronic myeloid leukemia 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 was deregulated in the absence of HDAC1. Their study also
found a regulatory crosstalk between HDAC1 and HDAC2 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 mRNA.
= 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 modifications. Protein phosphorylation is perhaps the
most widely studied and understood modification in which certain amino acid
residues are phosphorylated by the action of protein kinases or
dephosphorylated by the action of phosphatases. The acetylation 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 factors and co-regulators, some are not. Note the
following four examples: HDAC6 is associated with aggresomes.
Misfolded protein aggregates are tagged by ubiquitination and removed from the
cytoplasm by dynein 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.
PTEN is an important phosphatase involved in cell signaling via
phosphoinositols and the AKT/PI3 kinase 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 can repress its activity; on the converse,
deacetylation of PTEN by SIRT1 deacetylase and, by HDAC1, can stimulate
its activity. APE1/Ref-1 is a multifunctional protein
possessing both DNA repair activity and transcriptional regulatory activity
associated with oxidative stress. 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
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 gene. NF-κB 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 and HDAC6. These are just some examples of
constantly emerging non-histone, non-chromatin roles for HDACs.
HDAC inhibitors Histone deacetylase inhibitors have a
long history of use in psychiatry and neurology as mood stabilizers and
anti-epileptics, for example, valproic acid. In more recent times, HDIs are
being studied as a mitigator or treatment for neurodegenerative
diseases. Also in recent years, there has been an effort to develop HDIs for
cancer therapy. Vorinostat was approved in 2006 for the treatment of cutaneous
manifestations in patients with cutaneous T cell lymphoma that have
failed previous treatments. A second HDI, Istodax, was approved in 2009 for
patients with CTCL. The exact mechanisms by which the compounds may work are
unclear, but epigenetic 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. Recent research has focused on
developing isoform selective HDIs which can aid in elucidating role of
individual HDAC isoforms and device strategy for effective treatment of
diseases related to relevant HDAC isoform.
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 on HDACs acting on non-histone proteins, in each of those instances the
HDAC inhibitor Trichostatin A blocks the effect. HDIs have been shown to alter
the activity of many transcription factors, including ACTR, cMyb, E2F1,
EKLF, FEN 1, GATA, HNF-4, HSP90, Ku70, NFκB, PCNA, p53, RB, Runx, SF1 Sp3,
STAT, TFIIE, TCF, YY1. Research has shown that 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 infection. See also
Histone acetyltransferase Histone deacetylase inhibitor
Histone methyltransferase Histone-modifying enzymes
RNA polymerase control by chromatin structure
References External links
Histone deacetylase at the US National Library of Medicine Medical Subject
Headings Animation at Merck