3.5.1.- Histone deacetylases (HDACs): Introduction

Annotation status:  image of a grey circle Awaiting annotation/under development. Please contact us if you can help with annotation. » Email us

Histone deacetylases act as erasers of epigenetic acetylation marks on lysine residues in histones. Removal of the acetyl groups facilitates tighter packing of chromatin (heterochromatin formation) leading to transcriptional repression.

The histone deacetylase family has been classified in to five subfamilies based on phylogenetic comparison with yeast homologues:
Class I contains HDACs 1, 2, 3 and 8
Class IIa contains HDACs 4, 5, 7 and 9
Class IIb contains HDACs 6 and 10
Class III contains the sirtuins (SIRT1-7)
Class IV contains only HDAC11.
Classes I, II and IV use Zn+ as a co-factor, whereas catalysis by Class III enzymes requires NAD+ as a co-factor, and members of this subfamily have ADP-ribosylase activity in addition to protein deacetylase function [8].

HDACs have more general protein deacetylase activity, being able to deacetylate lysine residues in non-histone proteins [2] such as microtubules [3], the hsp90 chaperone [4] and the tumour suppressor p53 [6].

Dysregulated HDAC activity has been identified in cancer cells and tumour tissues [5,7], making HDACs attractive molecular targets in the search for novel mechanisms to treat cancer [12]. Several small molecule HDAC inhibitors are already approved for clinical use: , , , , , and . HDACs and HDAC inhibitors currently in development as potential anti-cancer therapeutics are reviewed by Simó-Riudalbas and Esteller (2015) [9].

Sirtuin-activating compounds (STACs) are receiving much attention as they appear to improve organ function, physical endurance, disease resistance and longevity in animal models, and have been shown to be safe and effective in treating inflammatory and metabolic disorders in non-human primates and in humans (see SRT2104 for example). The potential of STACs as life-extending/anti-ageing drugs is reviewed in [1]. In the sporting world the potential for SIRT1 activators to be used as (illcit) performance enhancers has not gone unnoticed, and is being monitored [10-11].

References

Show »

1. Bonkowski MS, Sinclair DA. (2016) Slowing ageing by design: the rise of NAD(+) and sirtuin-activating compounds. Nat. Rev. Mol. Cell Biol.17 (11): 679-690. [PMID:27552971]

2. Choudhary C, Kumar C, Gnad F, Nielsen ML, Rehman M, Walther TC, Olsen JV, Mann M. (2009) Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science325 (5942): 834-40. [PMID:19608861]

3. Hubbert C, Guardiola A, Shao R, Kawaguchi Y, Ito A, Nixon A, Yoshida M, Wang XF, Yao TP. (2002) HDAC6 is a microtubule-associated deacetylase. Nature417 (6887): 455-8. [PMID:12024216]

4. Kovacs JJ, Murphy PJ, Gaillard S, Zhao X, Wu JT, Nicchitta CV, Yoshida M, Toft DO, Pratt WB, Yao TP. (2005) HDAC6 regulates Hsp90 acetylation and chaperone-dependent activation of glucocorticoid receptor. Mol. Cell18 (5): 601-7. [PMID:15916966]

5. Lin RJ, Sternsdorf T, Tini M, Evans RM. (2001) Transcriptional regulation in acute promyelocytic leukemia. Oncogene20 (49): 7204-15. [PMID:11704848]

6. Luo J, Su F, Chen D, Shiloh A, Gu W. (2000) Deacetylation of p53 modulates its effect on cell growth and apoptosis. Nature408 (6810): 377-81. [PMID:11099047]

7. Ropero S, Esteller M. (2007) The role of histone deacetylases (HDACs) in human cancer. Mol Oncol1 (1): 19-25. [PMID:19383284]

8. Sauve AA. (2010) Sirtuin chemical mechanisms. Biochim. Biophys. Acta1804 (8): 1591-603. [PMID:20132909]

9. Simó-Riudalbas L, Esteller M. (2015) Targeting the histone orthography of cancer: drugs for writers, erasers and readers. Br. J. Pharmacol.172 (11): 2716-32. [PMID:25039449]

10. Thevis M, Kuuranne T, Walpurgis K, Geyer H, Schänzer W. (2016) Annual banned-substance review: analytical approaches in human sports drug testing. Drug Test Anal8 (1): 7-29. [PMID:26767774]

11. Thevis M, Schänzer W. (2016) Emerging drugs affecting skeletal muscle function and mitochondrial biogenesis - Potential implications for sports drug testing programs. Rapid Commun. Mass Spectrom.30 (5): 635-51. [PMID:26842585]

12. West AC, Johnstone RW. (2014) New and emerging HDAC inhibitors for cancer treatment. J. Clin. Invest.124 (1): 30-9. [PMID:24382387]

How to cite this page

To cite this family introduction, please use the following:

3.5.1.- Histone deacetylases (HDACs), introduction. Last modified on 31/03/2017. Accessed on 20/10/2017. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/FamilyIntroductionForward?familyId=848.