Histone deacetylase inhibitor

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 acetylates 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. [ Thiagalingam S, Cheng KH, Lee HJ, Mineva N, Thiagalingam A, Ponte JF (2003), Histone deacetylases: unique players in shaping the epigenetic histone code. Ann N Y Acad Sci 983, 84-100.
Marks PA, Richon VM, Rifkind RA (2000), Histone deacetylase inhibitors: inducers of differentiation or apoptosis of transformed cells. J Natl Cancer Inst 92, 1210-1216.]

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.

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, (iii) benzamides, (iv) electrophilic ketones, and (v) the aliphatic acid group of compounds such as phenylbutyrate and valproic acid. [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.] "Second generation" HDIs include SAHA (approved by the FDA in 2007 for leukemia therapy under the name "Vorinostat"), Belinostat/PXD101, MS275, LAQ824/LBH589, CI994, and MGCD0103. [cite journal |author=Beckers T, Burkhardt C, Wieland H, "et al" |title=Distinct pharmacological properties of second generation HDAC inhibitors with the benzamide or hydroxamate head group |journal=Int. J. Cancer |volume=121 |issue=5 |pages=1138–48 |year=2007 |doi=10.1002/ijc.22751] The sirtuin Class III HDACs are NAD+ dependent and are therefore inhibited by nicotinamide, as well derivatives of NAD, dihydrocoumarin, naphthopyranone, and 2-hydroxynaphaldehydes. [Porcu M, Chiarugi A (2005), The emerging therapeutic potential of sirtuin-interacting drugs: from cell death to lifespan extension. Trends Pharmacol Sci 26, 94-103.]

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, NFκB, PCNA, p53, RB, Runx, SF1 Sp3, STAT, TFIIE, TCF, YY1, etc. [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.
Yang XJ, Seto E (2007), HATs and HDACs: from structure, function and regulation to novel strategies for therapy and prevention. Oncogene 26, 5310-5318.]

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 neurodegenerative diseases. [Hahnen E, Hauke J, Tränkle C, Eyüpoglu IY, Wirth B, Blümcke I (2008), Histone deacetylase inhibitors: possible implications for neurodegenerative disorders. Expert Opin Investig Drugs 17(2):169-84]

Also in recent years, there has been an effort to develop HDIs as a cancer treatment or adjunct [cite journal |author=Marks PA, Dokmanovic M |title=Histone deacetylase inhibitors: discovery and development as anticancer agents |journal=Expert opinion on investigational drugs |volume=14 |issue=12 |pages=1497–511 |year=2005 |doi=10.1517/13543784.14.12.1497] The exact mechanisms by which the compounds may work are unclear, but epigenetic pathways are proposed. [cite journal | author = Claude Monneret | title = Histone deacetylase inhibitors for epigenetic therapy of cancer | journal = Anticancer Drugs | volume = 18 | pages = 363–70 | date = April 2007 | doi = 10.1097/CAD.0b013e328012a5db] 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. [ Richon VM, Sandhoff TW, Rifkind RA, Marks PA (2000), Histone deacetylase inhibitor selectively induces p21(WAF1) expression and gene-associated histone acetylation. Proc Natl Acad Sci USA 97(18):10014-10019. ] The pRb protein is part of a complex which attracts HDACs to the chromatin so that it will deacetylate histones.Brehm A, Miska EA, McCance DJ, Reid JL, Bannister AJ, Kouzarides T. 1998 Retinoblastoma protein recruits histone deacetylase to repress transcription. Nature 391(6667):597-601.] HDAC1 negatively regulates the cardiovascular transcription factor Kruppel-like factor 5 through direct interaction. Matsumura T, Suzuki T, Aizawa K, Munemasa Y, Muto S, Horikoshi M, Nagai R 2005 The deacetylase HDAC1 negatively regulates the cardiovascular transcription factor Kruppel-like factor 5 through direct interaction. J Bio Chem 280(13):12123-9 ] 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. [ Zhang Z, Yamashita H, Toyama T, Sugiura H, Ando Y, Mita K, Hamaguchi M, Hara Y, Kobayashi S, Iwase H (2005), Quantitation of HDAC1 mRNA expression in invasive carcinoma of the breast. Breast Cancer Res Treat 94(1):11-6.]

References