Histone deacetylase inhibitor: Wikis

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

Contents

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. [1]

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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[2]:

  1. hydroxamic acids, such as trichostatin A,
  2. cyclic tetrapeptides (such as trapoxin B), and the depsipeptides,
  3. benzamides,
  4. electrophilic ketones, and
  5. 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).[3][4]

The sirtuin Class III HDACs are NAD+ dependent and are therefore inhibited by nicotinamide, as well derivatives of NAD, dihydrocoumarin, naphthopyranone, and 2-hydroxynaphaldehydes.[5]

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. [2][6]

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 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.[7] 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.[8] 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 sirtuins.[9]

Cancer treatment

Also in recent years, there has been an effort to develop HDIs as a cancer treatment or adjunct[10] [11] The exact mechanisms by which the compounds may work are unclear, but epigenetic pathways are proposed.[12] 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.[13] The pRb protein is part of a complex which attracts HDACs to the chromatin so that it will deacetylate histones.[14] HDAC1 negatively regulates the cardiovascular transcription factor Kruppel-like factor 5 through direct interaction.[15] 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.[16]

Other diseases

References

  1. ^ 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.  
  2. ^ a b 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.  
  3. ^ 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): 1138–48. doi:10.1002/ijc.22751.  
  4. ^ 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.  
  5. ^ 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.  
  6. ^ 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.  
  7. ^ 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:10.1517/13543784.17.2.169. PMID 18230051. http://www.informapharmascience.com/doi/abs/10.1517/13543784.17.2.169.  
  8. ^ 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.  
  9. ^ 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.  
  10. ^ Marks PA, Dokmanovic M (2005). "Histone deacetylase inhibitors: discovery and development as anticancer agents". Expert opinion on investigational drugs 14 (12): 1497–511. doi:10.1517/13543784.14.12.1497.  
  11. ^ http://clincancerres.aacrjournals.org/content/8/3/662.full.pdf "Histone Deacetylase Inhibitors: A New Class of Potential Therapeutic Agents for Cancer Treatment" 2002
  12. ^ Claude Monneret (April 2007). "Histone deacetylase inhibitors for epigenetic therapy of cancer". Anticancer Drugs 18: 363–70. doi:10.1097/CAD.0b013e328012a5db.  
  13. ^ 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.  
  14. ^ 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.  
  15. ^ 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.  
  16. ^ 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.  
  17. ^ http://clinicaltrials.gov/ct2/show/NCT00606307 "Phase IIA Study of the HDAC Inhibitor ITF2357 in Patients With JAK-2 V617F Positive Chronic Myeloproliferative Diseases"

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