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.

Discovering the landscape of protein modifications

“…Widespread epigenetic modifications can regulate almost all of the hallmarks of cancer (Hanahan and Weinberg, 2011). Specifically, targeting the enzymes responsible for histone lysine deacetylation (HDACs or KDACs) has led to new U.S. Food and Drug Administration (FDA)-approved chemotherapeutics (Li et al, 2020), and investigation of the functional effects of histone modifications has provided mechanistic insight into their cellular effects. For example, hyperacetylation of histones H3 and H4 is required for expression of the cell cycle inhibitor p21, and this protein modification was found to be reversed in cancer cells with high levels of HDAC expression (Gui et al, 2004).…”

“…Treatment with the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA; vorinostat) reverses the loss of H3/4 lysine acetylation, reducing Myc protomer occupancy and increasing p21 expression, which leads to reduced cancer cell proliferation. Vorinostat (among other HDAC inhibitors) has been FDA approved as an anticancer agent for cutaneous T cell lymphoma since 2006, with many more HDAC inhibitors being evaluated in clinical trials for a variety of cancer types (reviewed by Li et al, 2020).…”

Overexpression of Human ABCB1 and ABCG2 Reduces the Susceptibility of Cancer Cells to the Histone Deacetylase 6-Specific Inhibitor Citarinostat

“…Histone deacetylases (HDACs) are a family of enzymes that remove acetyl groups from the acetylated histone and non-histone proteins, leading to chromatin condensation and transcriptional repression [ 1 ]. Many important cellular processes such as transcriptional regulation, cell cycle control, DNA damage repair, apoptosis, and autophagy are regulated by HDACs [ 2 ]. Consequently, the dysregulation of HDAC activity can cause abnormal gene expression and cell signaling that promote tumor cell initiation and proliferation, making the HDACs promising therapeutic targets for drug discovery [ 2 , 3 , 4 ].…”

“…Many important cellular processes such as transcriptional regulation, cell cycle control, DNA damage repair, apoptosis, and autophagy are regulated by HDACs [ 2 ]. Consequently, the dysregulation of HDAC activity can cause abnormal gene expression and cell signaling that promote tumor cell initiation and proliferation, making the HDACs promising therapeutic targets for drug discovery [ 2 , 3 , 4 ]. Non-selective pan-HDAC inhibitors panobinostat (LBH589) and belinostat (PXD101) have been approved by the U.S. Food and Drug Administration (FDA) for use in patients with multiple myeloma (MM) [ 5 ] and relapsed or refractory peripheral T-cell lymphoma [ 6 ], respectively.…”

Dual G9A and EZH2 inhibition stimulates an anti-tumour immune response in ovarian high-grade serous carcinoma

“…HGSC cells can evade immune responses by altering their epigenome, and targeting ovarian cancer epigenetics can reactivate cancer testis antigens (3)(4)(5), induce viral mimicry (6,7) and alter the tumour immune microenvironment and immune cell function (8,9). DNA methylation and histone deacetylation are two mechanisms that play a role in cancer immune evasion (10,11), and, although inhibitors of both DNA methylation and histone deacetylation are currently used in some haematological malignancies, their use in solid malignancies has been limited due to toxicity and limited efficacy (12,13). More recently, histone methylation mediated by both G9A and EZH2 has been identified as an important pathway that influences the immune system in ovarian cancer and melanoma, as well as hepatocellular, multiple myeloma and bladder carcinomas (8,(14)(15)(16)(17)(18).…”