Histone Deacetylases (HDACs): Evolution, Specificity, Role in Transcriptional Complexes, and Pharmacological Actionability

Overview

Journal Genes (Basel)

Publisher MDPI

Date 2020 May 21

PMID 32429325

Citations 146

Authors

Giorgio Milazzo

Daniele Mercatelli

Giulia Di Muzio

Luca Triboli

Piergiuseppe De Rosa

Giovanni Perini

Federico M Giorgi

Affiliations

Soon will be listed here.

Abstract

Histone deacetylases (HDACs) are evolutionary conserved enzymes which operate by removing acetyl groups from histones and other protein regulatory factors, with functional consequences on chromatin remodeling and gene expression profiles. We provide here a review on the recent knowledge accrued on the zinc-dependent HDAC protein family across different species, tissues, and human pathologies, specifically focusing on the role of HDAC inhibitors as anti-cancer agents. We will investigate the chemical specificity of different HDACs and discuss their role in the human interactome as members of chromatin-binding and regulatory complexes.

Citing Articles

Genome-Wide Identification and Characterization of Histone Acetyltransferases and Deacetylases in Cucumber, and Their Implication in Developmental Processes.

Skarzynska-Lyzwa A, Turek S, Pisz M, Aparna , Plader W, Pawelkowicz M Genes (Basel). 2025; 16(2).

PMID: 40004456 PMC: 11855351. DOI: 10.3390/genes16020127.

HDAC10 and its implications in Sézary syndrome pathogenesis.

Pieniawska M, Rassek K, Skwara B, Zurawek M, Ziolkowska-Suchanek I, Visser L Front Cell Dev Biol. 2025; 13:1480192.

PMID: 39958888 PMC: 11825767. DOI: 10.3389/fcell.2025.1480192.

Regulation of HDAC6 Catalytic Activity in Cancer: The Role of Post-Translational Modifications and Protein-Protein Interactions.

Asaad L, Pepperrell B, McErlean E, Furlong F Int J Mol Sci. 2025; 26(3).

PMID: 39941046 PMC: 11818932. DOI: 10.3390/ijms26031274.

Histone deacetylases in the regulation of cell death and survival mechanisms in resistant BRAF-mutant cancers.

Biersack B, Nitzsche B, Hopfner M Cancer Drug Resist. 2025; 8:6.

PMID: 39935431 PMC: 11810460. DOI: 10.20517/cdr.2024.125.

HDAC1-3 inhibition triggers NEDD4-mediated CCR2 downregulation and attenuates immunosuppression in myeloid-derived suppressor cells.

Xie Z, Shao J, Shen Z, Ye Z, Okada Y, Okuzaki D Cancer Immunol Immunother. 2025; 74(3):81.

PMID: 39891718 PMC: 11787094. DOI: 10.1007/s00262-024-03931-y.

References

Lakowski B, Roelens I, Jacob S . CoREST-like complexes regulate chromatin modification and neuronal gene expression. J Mol Neurosci. 2006; 29(3):227-39. DOI: 10.1385/JMN:29:3:227. View

Li M, Van Esch B, Wagenaar G, Garssen J, Folkerts G, Henricks P . Pro- and anti-inflammatory effects of short chain fatty acids on immune and endothelial cells. Eur J Pharmacol. 2018; 831:52-59. DOI: 10.1016/j.ejphar.2018.05.003. View

Stuhmer T, Arts J, Chatterjee M, Borawski J, Wolff A, King P . Preclinical anti-myeloma activity of the novel HDAC-inhibitor JNJ-26481585. Br J Haematol. 2010; 149(4):529-36. DOI: 10.1111/j.1365-2141.2010.08126.x. View

Guarente L . Sir2 links chromatin silencing, metabolism, and aging. Genes Dev. 2000; 14(9):1021-6. View

Zhang Y, Xu Q, Liu G, Huang H, Lin W, Huang Y . Effect of histone deacetylase on prostate carcinoma. Int J Clin Exp Pathol. 2016; 8(11):15030-4. PMC: 4713626. View

Kumar S, Stecher G, Li M, Knyaz C, Tamura K . MEGA X: Molecular Evolutionary Genetics Analysis across Computing Platforms. Mol Biol Evol. 2018; 35(6):1547-1549. PMC: 5967553. DOI: 10.1093/molbev/msy096. View

Kim S, Thiessen P, Bolton E, Chen J, Fu G, Gindulyte A . PubChem Substance and Compound databases. Nucleic Acids Res. 2015; 44(D1):D1202-13. PMC: 4702940. DOI: 10.1093/nar/gkv951. View

Zhou H, Cai Y, Liu D, Li M, Sha Y, Zhang W . Pharmacological or transcriptional inhibition of both HDAC1 and 2 leads to cell cycle blockage and apoptosis via p21 and p19 upregulation in hepatocellular carcinoma. Cell Prolif. 2018; 51(3):e12447. PMC: 6528930. DOI: 10.1111/cpr.12447. View

Jia D, Augert A, Kim D, Eastwood E, Wu N, Ibrahim A . Loss Drives Small Cell Lung Cancer and Increases Sensitivity to HDAC Inhibition. Cancer Discov. 2018; 8(11):1422-1437. PMC: 6294438. DOI: 10.1158/2159-8290.CD-18-0385. View

10.

Kalin J, Wu M, Gomez A, Song Y, Das J, Hayward D . Targeting the CoREST complex with dual histone deacetylase and demethylase inhibitors. Nat Commun. 2018; 9(1):53. PMC: 5754352. DOI: 10.1038/s41467-017-02242-4. View

11.

Li Y, Seto E . HDACs and HDAC Inhibitors in Cancer Development and Therapy. Cold Spring Harb Perspect Med. 2016; 6(10). PMC: 5046688. DOI: 10.1101/cshperspect.a026831. View

12.

Ganai S . Histone Deacetylase Inhibitors Modulating Non-epigenetic Players: The Novel Mechanism for Small Molecule Based Therapeutic Intervention. Curr Drug Targets. 2016; 19(6):593-601. DOI: 10.2174/1389450117666160527143257. View

13.

Grausenburger R, Bilic I, Boucheron N, Zupkovitz G, El-Housseiny L, Tschismarov R . Conditional deletion of histone deacetylase 1 in T cells leads to enhanced airway inflammation and increased Th2 cytokine production. J Immunol. 2010; 185(6):3489-97. PMC: 3175530. DOI: 10.4049/jimmunol.0903610. View

14.

Millard C, Watson P, Fairall L, Schwabe J . Targeting Class I Histone Deacetylases in a "Complex" Environment. Trends Pharmacol Sci. 2017; 38(4):363-377. DOI: 10.1016/j.tips.2016.12.006. View

15.

Stiegler P, De Luca A, Bagella L, Giordano A . The COOH-terminal region of pRb2/p130 binds to histone deacetylase 1 (HDAC1), enhancing transcriptional repression of the E2F-dependent cyclin A promoter. Cancer Res. 1998; 58(22):5049-52. View

16.

Cheng Y, Liao L, Yang Q, Chen Y, Nie P, Zhang X . The histone deacetylase inhibitor panobinostat exerts anticancer effects on esophageal squamous cell carcinoma cells by inducing cell cycle arrest. Cell Biochem Funct. 2018; 36(8):398-407. DOI: 10.1002/cbf.3359. View

17.

Hayakawa T, Nakayama J . Physiological roles of class I HDAC complex and histone demethylase. J Biomed Biotechnol. 2010; 2011:129383. PMC: 2964911. DOI: 10.1155/2011/129383. View

18.

Chung V, Tan T, Ye J, Huang R, Lai H, Kappei D . The role of GRHL2 and epigenetic remodeling in epithelial-mesenchymal plasticity in ovarian cancer cells. Commun Biol. 2019; 2:272. PMC: 6656769. DOI: 10.1038/s42003-019-0506-3. View

19.

Nio K, Yamashita T, Okada H, Kondo M, Hayashi T, Hara Y . Defeating EpCAM(+) liver cancer stem cells by targeting chromatin remodeling enzyme CHD4 in human hepatocellular carcinoma. J Hepatol. 2015; 63(5):1164-72. DOI: 10.1016/j.jhep.2015.06.009. View

20.

Mondello P, Tadros S, Teater M, Fontan L, Chang A, Jain N . Selective Inhibition of HDAC3 Targets Synthetic Vulnerabilities and Activates Immune Surveillance in Lymphoma. Cancer Discov. 2020; 10(3):440-459. PMC: 7275250. DOI: 10.1158/2159-8290.CD-19-0116. View