Histone deacetylase inhibitor

# Overview
Histone deacetylase inhibitors (HDAC inhibitors, HDI) are a class of compounds that interfere with the function of histone deacetylase.

# Cellular Biochemistry / Pharmacology
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 expression. 

## HDAC classification
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 gene;
- 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.

# HDI classification
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:
- (i) hyroxamic acids, such as Trichostatin A,
- (ii) cyclic tetrapeptides (such as trapoxin B), and the depsipeptides,
- (iii) benzamides,
- (iv) electrophilic ketones, and
- (v) the aliphatic acid compounds such as phenylbutyrate and valproic acid.
"Second generation" HDIs include SAHA/Vorinostat, Belinostat/PXD101, MS275, LAQ824/LBH589, CI994, and 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.

# Additional functions
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, NFB, PCNA, p53, RB, Runx, SF1 Sp3, STAT, TFIIE, TCF, YY1, etc. 

# Uses
HDIs have a long history of use in psychiatry and neurology as mood stabilzers and anti-epileptics.  The prime example of this is valproic acid, marketed as a drug under the names of Depakene, Depakote, and Divalproex.  More recently, HDIs are being studied as a mitigator for neurodegenerative diseases.

## Cancer treatment
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 supressor 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 deacetylate histones.   HDAC1 negatively regulates the cardiovascular transcription factor Kruppel-like factor 5 through direct interaction.  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 (ER).  Recent data indicate that chromatin inactivation mediated by HDAC and DNA methylation is a critical component of ER silencing in human breast cancer cells.
Vorinostat was licenced by the FDA in Oct 2006 for the treatment of cutaneous T cell lymphoma (CTCL).
Valproic acid in under investigation for various cancers including leukemia.