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 [23].

HDACs have more general protein deacetylase activity, being able to deacetylate lysine residues in non-histone proteins [3] such as microtubules [10], the hsp90 chaperone [13] and the tumour suppressor p53 [16].

Dysregulated HDAC activity has been identified in cancer cells and tumour tissues [14,21], making HDACs attractive molecular targets in the search for novel mechanisms to treat cancer [27]. Several small molecule HDAC inhibitors are already approved for clinical use: romidepsin, belinostat, vorinostat, panobinostat, belinostat, valproic acid and tucidinostat. HDACs and HDAC inhibitors currently in development as potential anti-cancer therapeutics are reviewed by Simó-Riudalbas and Esteller (2015) [24].

* Key recommended reading is highlighted with an asterisk

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* Fiorentino F, Mai A, Rotili D. (2021) Emerging Therapeutic Potential of SIRT6 Modulators. J Med Chem, 64 (14): 9732-9758. [PMID:34213345]

* Ho TCS, Chan AHY, Ganesan A. (2020) Thirty Years of HDAC Inhibitors: 2020 Insight and Hindsight. J Med Chem, 63 (21): 12460-12484. [PMID:32608981]

* Kunadis E, Lakiotaki E, Korkolopoulou P, Piperi C. (2021) Targeting post-translational histone modifying enzymes in glioblastoma. Pharmacol Ther, 220: 107721. [PMID:33144118]

* Liu T, Wan Y, Xiao Y, Xia C, Duan G. (2020) Dual-Target Inhibitors Based on HDACs: Novel Antitumor Agents for Cancer Therapy. J Med Chem, 63 (17): 8977-9002. [PMID:32320239]

Maolanon AR, Kristensen HM, Leman LJ, Ghadiri MR, Olsen CA. (2017) Natural and Synthetic Macrocyclic Inhibitors of the Histone Deacetylase Enzymes. Chembiochem, 18 (1): 5-49. [PMID:27748555]

Micelli C, Rastelli G. (2015) Histone deacetylases: structural determinants of inhibitor selectivity. Drug Discov Today, 20 (6): 718-35. [PMID:25687212]

Millard CJ, Watson PJ, Fairall L, Schwabe JWR. (2017) Targeting Class I Histone Deacetylases in a "Complex" Environment. Trends Pharmacol Sci, 38 (4): 363-377. [PMID:28139258]

Roche J, Bertrand P. (2016) Inside HDACs with more selective HDAC inhibitors. Eur J Med Chem, 121: 451-483. [PMID:27318122]

Tang J, Yan H, Zhuang S. (2013) Histone deacetylases as targets for treatment of multiple diseases. Clin Sci, 124 (11): 651-62. [PMID:23414309]

Walkinshaw DR, Tahmasebi S, Bertos NR, Yang XJ. (2008) Histone deacetylases as transducers and targets of nuclear signaling. J Cell Biochem, 104 (5): 1541-52. [PMID:18425769]

Zagni C, Floresta G, Monciino G, Rescifina A. (2017) The Search for Potent, Small-Molecule HDACIs in Cancer Treatment: A Decade After Vorinostat. Med Res Rev, 37 (6): 1373-1428. [PMID:28181261]

* Zhang XH, Qin-Ma, Wu HP, Khamis MY, Li YH, Ma LY, Liu HM. (2021) A Review of Progress in Histone Deacetylase 6 Inhibitors Research: Structural Specificity and Functional Diversity. J Med Chem, 64 (3): 1362-1391. [PMID:33523672]

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