The Roles of Histone Deacetylases and Their Inhibitors in Cancer Therapy

Abstract

Genetic mutations and abnormal gene regulation are key mechanisms underlying tumorigenesis. Nucleosomes, which consist of DNA wrapped around histone cores, represent the basic units of chromatin. The fifth amino group (N^ε) of histone lysine residues is a common site for post-translational modifications (PTMs), and of these, acetylation is the second most common. Histone acetylation is modulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs), and is involved in the regulation of gene expression. Over the past two decades, numerous studies characterizing HDACs and HDAC inhibitors (HDACi) have provided novel and exciting insights concerning their underlying biological mechanisms and potential anti-cancer treatments. In this review, we detail the diverse structures of HDACs and their underlying biological functions, including transcriptional regulation, metabolism, angiogenesis, DNA damage response, cell cycle, apoptosis, protein degradation, immunity and other several physiological processes. We also highlight potential avenues to use HDACi as novel, precision cancer treatments.

Keywords: HDAC; HDAC inhibitors; HDAC sequence; cancer therapy; histone modification.

FIGURE 1

Domain structure of human HDACs. The fundamental structure of all deacetylases. Total number of amino acid residues and molecular weights in each HDAC were shown on the right of each protein.

FIGURE 2

Transcription regulation in HDACs and HDACi. (A) HDAC and HDACi involved transcription regulation in concert with other epigenetic modifiers. (B) A working model described how HDAC and HDACi regulate both of oncogenes and tumor suppressor genes expression.

FIGURE 3

HDAC-involved metabolic regulation. HDACs regulate metabolism mainly including glycometabolism, lipid metabolism, amino acid metabolism and redox.

FIGURE 4

Overview of HDAC-involved biological functions and therapeutic targets. An overview of HDAC-involved biological functions including transcription, metabolism, oxidative stress, redox, protein degradation, cell cycle, DNA damage repair, apoptosis, angiogenesis, EMT, immunity, and stemness. There diverse functions could establish single or synergistic therapeutic targets.