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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.
Thiagalingam S, Cheng KH, Lee HJ,
Mineva N, Thiagalingam A, Ponte JF (March 2003). "Histone deacetylases: unique
players in shaping the epigenetic histone code". Ann. N. Y.
Acad. Sci. 983: 84–100. PMID 12724214. http://www3.interscience.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0077-8923&date=2003&volume=983&spage=84.
Marks PA, Richon VM, Rifkind RA
(August 2000). "Histone deacetylase
inhibitors: inducers of differentiation or apoptosis of transformed
cells". J. Natl. Cancer Inst. 92
(15): 1210–6. PMID 10922406. http://jnci.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=10922406.
- ^ a
Drummond DC, Noble CO, Kirpotin DB,
Guo Z, Scott GK, Benz CC (2005). "Clinical development of
histone deacetylase inhibitors as anticancer agents". Annu.
Rev. Pharmacol. Toxicol. 45: 495–528. doi:10.1146/annurev.pharmtox.45.120403.095825.
PMID 15822187. http://arjournals.annualreviews.org/doi/abs/10.1146/annurev.pharmtox.45.120403.095825?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dncbi.nlm.nih.gov.
Beckers T, Burkhardt C, Wieland H,
et al (2005). "Distinct pharmacological properties of
second generation HDAC inhibitors with the benzamide or hydroxamate
head group". Int. J. Cancer 121 (5):
- ^ Acharya MR, Sparreboom A, Venitz J, Figg
WD (2008). "Rational development of histone deacetylase inhibitors
as anticancer agents: a review". Mol Pharmacol
68 (4): 917–32. doi:10.1124/mol.105.014167. PMID 15955865.
Porcu M, Chiarugi A (February 2005).
"The emerging therapeutic
potential of sirtuin-interacting drugs: from cell death to lifespan
extension". Trends Pharmacol. Sci. 26
(2): 94–103. doi:10.1016/j.tips.2004.12.009. PMID 15681027. http://linkinghub.elsevier.com/retrieve/pii/S0165-6147(04)00323-2.
Yang XJ, Seto E (August 2007). "HATs and HDACs: from
structure, function and regulation to novel strategies for therapy
and prevention". Oncogene 26 (37):
5310–8. doi:10.1038/sj.onc.1210599. PMID 17694074. http://dx.doi.org/10.1038/sj.onc.1210599.
Hahnen E, Hauke J, Tränkle C,
Eyüpoglu IY, Wirth B, Blümcke I (February 2008). "Histone deacetylase
inhibitors: possible implications for neurodegenerative
disorders". Expert Opin Investig Drugs
17 (2): 169–84. doi:10.1517/135437188.8.131.52. PMID 18230051. http://www.informapharmascience.com/doi/abs/10.1517/135437184.108.40.206.
- ^ Guan JS, Haggarty SJ, Giacometti E,
Dannenberg JH, Joseph N, Gao J, Nieland TJ, Zhou Y, Wang X,
Mazitschek R, Bradner JE, DePinho RA, Jaenisch R, Tsai LH (2009).
"HDAC2 negatively regulates memory formation and synaptic
plasticity". Nature 7 (7243): 55–60. doi:10.1038/nature07925. PMID 19424149.
- ^ Green KN, Steffan JS, Martinez-Coria H,
Sun X, Schreiber SS, Thompson LM, LaFerla FM (2008). "Nicotinamide
restores cognition in Alzheimer's disease transgenic mice via a
mechanism involving sirtuin inhibition and selective reduction of
Thr231-phosphotau.". J Neurosci 28 (45):
11500–10. doi:10.1523/JNEUROSCI.3203-08.2008. PMID 18987186.
Marks PA, Dokmanovic M (2005).
"Histone deacetylase inhibitors: discovery and development as
anticancer agents". Expert opinion on investigational
drugs 14 (12): 1497–511. doi:10.1517/135437220.127.116.117.
"Histone Deacetylase Inhibitors: A New Class of Potential
Therapeutic Agents for Cancer Treatment" 2002
Claude Monneret (April 2007).
"Histone deacetylase inhibitors for epigenetic therapy of cancer".
Anticancer Drugs 18: 363–70. doi:10.1097/CAD.0b013e328012a5db.
Richon VM, Sandhoff TW, Rifkind RA,
Marks PA (August 2000). "Histone deacetylase
inhibitor selectively induces p21WAF1 expression and
gene-associated histone acetylation". Proc. Natl. Acad.
Sci. U.S.A. 97 (18): 10014–9. doi:10.1073/pnas.180316197. PMID 10954755. PMC 27656. http://www.pnas.org/cgi/pmidlookup?view=long&pmid=10954755.
- ^ Brehm A, Miska EA, McCance DJ, Reid JL,
Bannister AJ, Kouzarides T (February 1998). "Retinoblastoma protein
recruits histone deacetylase to repress transcription".
Nature 391 (6667): 597–601. doi:10.1038/35404. PMID 9468139.
- ^ Matsumura T, Suzuki T, Aizawa K, et
al. (April 2005). "The deacetylase HDAC1
negatively regulates the cardiovascular transcription factor
Krüppel-like factor 5 through direct interaction". J. Biol.
Chem. 280 (13): 12123–9. doi:10.1074/jbc.M410578200. PMID 15668237. http://www.jbc.org/cgi/pmidlookup?view=long&pmid=15668237.
Zhang Z, Yamashita H, Toyama T,
et al. (November 2005). "Quantitation of HDAC1 mRNA
expression in invasive carcinoma of the breast*". Breast Cancer
Res. Treat. 94 (1): 11–6. doi:10.1007/s10549-005-6001-1. PMID 16172792.
"Phase IIA Study of the HDAC Inhibitor ITF2357 in Patients With
JAK-2 V617F Positive Chronic Myeloproliferative Diseases"