Role of histone deacetylases and their inhibitors in cancer biology and treatment

Abstract

Histone deacetylase (HDAC) inhibitors constitute a new group of epigenetic agents that has gained much attention in cancer drug development. Research in the field of epigenetics is furthering our understanding of malignant behavior and providing novel targets to improve the outcomes of cancer therapy. In this review we present an overview of the complex landscape of HDAC inhibitor development starting from a discussion of the various HDAC isotypes and their roles in cancer biology, to mechanisms of action of HDAC inhibitors and their current state of development. The large gamut of HDACs are classified into 3 classes of "classical HDACs" and the "sirtuins" but in general lack specificity of deacetylation targets as they deacetylate both histone and non-histone targets. This non-specifity underlies the pleiotropic effects of HDAC inhibitors that does not stop at alteration of gene expression but extends into a wide array of cellular (nuclear and/or cytoplasmic) processes. The potential of HDAC inhibitors for cancer therapy has been explored in preclinical models and has reached the clinic as some agents are FDA-approved in hematologic malignancies where they function as differentiation agents. In solid tumors, HDAC inhibitors are used in combination with chemotherapy, which raises issues of mechanisms of potentiation and optimal administration (schedule and dose). Lastly, we discuss the need for biomarker development which will facilitate and guide the rational development of HDAC inhibitors as anticancer therapy.