Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer

Abstract

Histone deacetylases (HDACs) and histone acetylases (HATs) are enzymes that are responsible for deacetylating and acetylating, respectively, the amino-terminal tails of histones. These chromatin changes regulate transcription and many other nuclear events. Non-histone proteins (such as the oncosuppressor p53) and several cytoplasmic proteins are also regulated by HATs/HDACs. Studies on the molecular pathogenesis of acute myeloid leukaemias have shown that the aberrant recruitment of HDACs has an important role in leukaemogenesis. Leukaemia-associated fusion proteins (such as promyelocytic leukaemia (PML)–retinoic acid receptor (RAR) and acute myeloid leukaemia 1 (AML1)–ETO) recruit HDACs to repress the transcription of genes involved in differentiation (the fusion proteins therefore block differentiation) and impair the function of p53. Alterations in the expression and/or activity of HATs/HDACs have been also observed in solid tumours. Solid tumours show decreased levels of histone acetylation, which correlates with clinical outcome. HDAC inhibitors (HDACi) have been widely studied and belong to several chemical classes. HDACi exert cell-type-specific effects inducing apoptosis, cell-cycle arrest, and differentiation. In leukaemias, HDACi induce the expression of members of the tumour-necrosis factor-related apoptosis-inducing ligand (TRAIL) and FAS death receptor pathways. This induction is responsible for the pro-apoptotic effects of HDACi. Clinical trials for several HDACi have started, and HDACi-responsive tumours have been observed.