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Histone deacetylase inhibitors (HDAC
inhibitors, HDI) are a class of compounds
with the function of histone deacetylase.
To carry out gene expression, a cell must control the coiling
and uncoiling of DNA around histones. This is accomplished with the
assistance of histone acetylases (HAT)
which acetylate the lysine residues in core histones leading to a
less compact and more transcriptionally active chromatin, and conversely the actions of histone deacetylases (HDAC) which remove
the acetyl groups from the lysine residues leading to the formation
of a condensed and transcriptionally silenced chromatin. Reversible
modification of the terminal tails of core histones constitutes the
major epigenetic mechanism for remodeling higher
order chromatin structure and controlling gene
expression. HDAC inhibitors (HDI) block this action and can
result in hyperacetylation of histones, therefore affecting gene
HDACs are classified in four groups based on their homology to
yeast histone deacetylases:
- Class I which includes HDAC1, -2, -3
and -8 are related to yeast RPD3
- Class II which includes HDAC4, -5, -6,
-7, -9 and -10 are related to yeast Hda1 gene;
- Class III, also known as the sirtuins are related to
the Sir2 gene and include SIRT1-7, and
- Class IV which contains only HDAC11 has features of both Class I and II.
The “classical” HDIs act exclusively on Class I and Class II
HDACs by binding to the zinc containing catalytic domain of the
HDACs. These classical HDIs fall into several groupings, in order
of decreasing potency:
- hydroxamic acids, such as trichostatin A,
- cyclic tetrapeptides (such as trapoxin B), and the depsipeptides,
- electrophilic ketones,
- the aliphatic acid compounds such as phenylbutyrate and valproic acid.
"Second generation" HDIs include the hydroxamic acids vorinostat (SAHA), belinostat (PXD101), LAQ824, and panobinostat(LBH589);
and the benzamides entinostat (MS275),
CI994, and mocetinostat (MGCD0103).
The sirtuin Class III HDACs are NAD+ dependent and are therefore
inhibited by nicotinamide, as well derivatives of NAD,
dihydrocoumarin, naphthopyranone, and 2-hydroxynaphaldehydes.
HDIs should not be considered to act solely as enzyme inhibitors
of HDACs. A large variety of nonhistone transcription factors and
transcriptional co-regulators are known to be modified by
acetylation. HDIs can alter the degree of acetylation nonhistone
effector molecules and thereby increase or repress the
transcription of genes by this mechanism. Examples include: ACTR, cMyb, E2F1, EKLF, FEN 1, GATA, HNF-4, HSP90, Ku70, NFκB, PCNA, p53, RB, Runx, SF1 Sp3, STAT, TFIIE, TCF,
YY1, etc. 
HDIs have a long history of use in psychiatry and neurology as
mood stabilzers and anti-epileptics. The prime example of this is
marketed as a drug under the trade names Depakene,
Depakote, and Divalproex. More recently, HDIs are
being studied as a mitigator for neurodegenerative diseases such as Alzheimer's disease and Huntington's disease.
Enhancement of memory formation is increased in mice given the HDIs
sodium butyrate or SAHA, or by genetic knockout
of the HDAC2 gene in mice.
While that may have relevance to Alzheimer's disease, it was shown
that some cognitive deficits were restored in actual transgenic
mice that have a model of Alzheimer's disease (3xTg-AD) by orally
administered nicotinamide, a competitive HDI of Class III
Also in recent years, there has been an effort to develop HDIs
as a cancer treatment or adjunct  The
exact mechanisms by which the compounds may work are unclear, but
epigenetic pathways are proposed.
Richon et al. found that HDAC inhibitors can induce p21 (WAF1) expression, a regulator of p53's tumor suppressor activity. HDACs
are involved in the pathway by which the retinoblastoma protein (pRb)
suppresses cell proliferation. The
pRb protein is part of a complex which attracts HDACs to the chromatin so that it will
HDAC1 negatively regulates the cardiovascular transcription factor
Kruppel-like factor 5 through
Estrogen is well-established as a mitogenic factor
implicated in the tumorigenesis and progression of breast cancer via
its binding to the estrogen receptor alpha (ERα).
Recent data indicate that chromatin inactivation mediated by HDAC
and DNA methylation is a critical component of ERα silencing in
human breast cancer cells.
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JAK-2 V617F Positive Chronic Myeloproliferative Diseases"