Targeting histone deacetylases for cancer therapy: from molecular mechanisms to clinical implications

Abstract

Genetic abnormalities have been conventionally considered as hallmarks of cancer. However, studies over the past decades have demonstrated that epigenetic regulation also participates in the development of cancer. The fundamental patterns of epigenetic components, such as DNA methylation and histone modifications, are frequently altered in tumor cells. Acetylation is one of the best characterized modifications of histones, which is controlled by histone acetyltransferases (HATs) and histone deacetylases (HDACs). HDACs are a group of enzymes which catalyze the removal of the acetyl groups of both histones and non-histone proteins. HDACs are involved in modulating most key cellular processes, including transcriptional regulation, apoptosis, DNA damage repair, cell cycle control, autophagy, metabolism, senescence and chaperone function. Because HDACs have been found to function incorrectly in cancer, various HDAC inhibitors are being investigated to act as cancer chemotherapeutics. The primary purpose of this paper is to summarize recent studies of the links between HDACs and cancer, and further discuss the underlying mechanisms of anti-tumor activities of HDAC inhibitors and clinical implications.

Keywords: HDAC; HDAC inhibitor; cancer.; epigenetic therapy.

Figure 1

Biological functions of HDACs. Cellular functions regulated by HDACs, including apoptosis, DNA damage repair, cell cycle control, autophagy, metabolism, ageing and many others which are not listed above.

Figure 2

Role of HDACs in regulating apoptosis. HDACs function as apoptotic repressors, while treatment of HDAC inhibitors upregulate pro-apoptotic proteins such as Bad and downregulate anti-apoptotic proteins such as Bcl-2. HDAC inhibitors promote tumor cell apoptosis through both intrinsic and extrinsic pathways. *Arrows in black mean 'promote' while the red ones mean 'inhibit', the same goes with all the figures below.

Figure 3

Role of HDACs in regulating DNA damage repair. HDACs interact with DNA damage responsive factors and promote DNA damage repair. HDAC inhibitors induce DNA damage through generation of ROS or suppression of DNA repair proteins.

Figure 4

Role of HDACs in regulating metabolism. HDACs regulate metabolism mainly through modulation of the acetylation level of metabolic proteins such as AMPK. Sirtuins can also regulate the NAD⁺/NADH ratio.