Histone deacetylase inhibitors and cell death

Abstract

Histone deacetylases (HDACs) are a vast family of enzymes involved in chromatin remodeling and have crucial roles in numerous biological processes, largely through their repressive influence on transcription. In addition to modifying histones, HDACs also target many other non-histone protein substrates to regulate gene expression. Recently, HDACs have gained growing attention as HDAC-inhibiting compounds are being developed as promising cancer therapeutics. Histone deacetylase inhibitors (HDACi) have been shown to induce differentiation, cell cycle arrest, apoptosis, autophagy and necrosis in a variety of transformed cell lines. In this review, we mainly discuss how HDACi may elicit a therapeutic response to human cancers through different cell death pathways, in particular, apoptosis and autophagy.

Fig. 1

The molecular mechanism of HDACi-induced cell death. So far, induction of apoptosis is the predominant route of HDACi-induced cell death. HDACi-mediated apoptosis is initiated by the hyperacetylation of histone and non-histone proteins: Core histone hyperacetylation results in an open chromatin that frequently correlates with gene activation. Non-histone protein acetylation can promote the induction of apoptosis by modulating protein function through altering their stability, cellular localization, and protein–nucleotide/protein–protein interactions. In particular, a series of transcription factors (including NF-κB, p53, and signal transducers and activators of transcription—STATs) are directly acetylated by HDACi, which augments their capacity to bind DNA and selectively modulate the expression of apoptotic genes. Through the combined effects on histone and non-histone acetylation, HDACi activates either extrinsic pathway (such as up-regulation of death receptors and/or ligand expression) and (or) intrinsic pathway (such as decreased expression of anti-apoptotic proteins Bcl2, Bcl-xL and enhanced expression of pro-apoptotic proteins Bax, Bak) to induce apoptosis. HDACi can augment p21 expression in tumor cells, which can influence the decision of tumor cells to undergo apoptosis and/or cell cycle arrest following HDACi treatment. Moreover, HDACi treatment causes the generation of ROS through Trx down-regulation to possibly initiate or enhance apoptotic signalling in tumor cells. More recently, HDACi has been shown to induce tumor cell death with morphological features of autophagy, although there are doubts regarding the importance of autophagy and the pro-survival/pro-death function of autophagy in regulating the anti-tumor responses of HDACi. Several signaling pathways including ROS regulate HDACi-mediated autophagy. Another possibility is that HDACi may induce necrosis in tumor cells