Naturally Occurring Histone Deacetylase (HDAC) Inhibitors in the Treatment of Cancers

Abstract

Histone deacetylases (HDACs) are well-reported epigenetic regulators of gene expression. HDACs remove acetyl groups from histones thereby enhancing the compactness of the DNA to repress gene expression. Studying the role of HDACs in disease development is very critical. HDACs are classified into four major classes based on their homology to yeast HDAC proteins. HDACs that deacetylate acetylated histones are Class I, Class II and Class IV enzymes; and the one that deacetylate even non-histone proteins such as p53 and α-tubulin are Class III HDACs, known as sirtuins (SIRTs). HDACs regulate cell division, apoptosis, differentiation, migration and angiogenesis. Deregulation of HDACs is reported in many cancers. Targeted inhibition of HDACs impede cancer cell growth, proliferation and metastatic spread of tumor cells. Accordingly, many natural and synthetic HDAC inhibitors have been developed and tested for inhibiting tumors. However, only few have shown success in clinical trials. This chapter covers: (a) the fundamentals of histone acetylation and deacetylation mechanisms, key proteins and processes involved in the regulation of these reactions; (b) the role of HDACs in the pathogenesis of cancers; and (c) the classification of HDAC inhibitors (HDACis), effect of HDACis on the immune system and recent advancements in their development from natural sources. Finally, an account on U.S. FDA-approved HDACis is provided.