Targeting Histone Deacetylases: Opportunities for Cancer Treatment and Chemoprevention

Abstract

The dysregulation of gene expression is a critical event involved in all steps of tumorigenesis. Aberrant histone and non-histone acetylation modifications of gene expression due to the abnormal activation of histone deacetylases (HDAC) have been reported in hematologic and solid types of cancer. In this sense, the cancer-associated epigenetic alterations are promising targets for anticancer therapy and chemoprevention. HDAC inhibitors (HDACi) induce histone hyperacetylation within target proteins, altering cell cycle and proliferation, cell differentiation, and the regulation of cell death programs. Over the last three decades, an increasing number of synthetic and naturally derived compounds, such as dietary-derived products, have been demonstrated to act as HDACi and have provided biological and molecular insights with regard to the role of HDAC in cancer. The first part of this review is focused on the biological roles of the Zinc-dependent HDAC family in malignant diseases. Accordingly, the small-molecules and natural products such as HDACi are described in terms of cancer therapy and chemoprevention. Furthermore, structural considerations are included to improve the HDACi selectivity and combinatory potential with other specific targeting agents in bifunctional inhibitors and proteolysis targeting chimeras. Additionally, clinical trials that combine HDACi with current therapies are discussed, which may open new avenues in terms of the feasibility of HDACi’s future clinical applications in precision cancer therapies.

The Impact of Fluorination on the Design of Histone Deacetylase Inhibitors

“…Currently, HDACs increasingly prove to play an important role in cancer via chromatin-modifying complexes and modulating gene expression [ 10 ]. Therefore, these enzymes become potential and attractive targets in the research and development of new anticancer drugs [ 9 ].…”

“…This is accompanied by an increased affinity for the negatively charged phosphate backbone of the DNA, ultimately resulting in a downregulation of its transcription. The dysregulation of gene expression, which is actually mediated by HDACs, is known to occur in a variety of cancers [ 10 ]. The abnormal activation of HDACs can be targeted by HDAC inhibitors (HDACis).…”

HDAC Class I Inhibitor Domatinostat Preferentially Targets Glioma Stem Cells over Their Differentiated Progeny

“…To date, 18 HDACs have been identified and are categorized into four classes (I through IV). To overcome the issues arising from the lack of selectivity of classical broad-spectrum HDAC inhibitors that target multiple classes of HDACs (such as trichostatin A and valproic acid), the development of class- or isoform-selective HDAC inhibitors have been actively sought [ 29 , 30 ]. Domatinostat (4SC-202), whose effects on glioma cells we tested in the present study, is one such class-selective HDAC inhibitor that selectively targets class I HDACs [ 11 , 12 , 13 ].…”

Insights Into the Properties, Biological Functions, and Regulation of USP21

“…In addition, the STAT3 inhibitor cryptotanshinone and HDAC inhibitors (SAHA and MS-275) have been reported to downregulate the expression of USP21 ( Table 5 ) ( Jin et al, 2016 ; Lee et al, 2021 ). Although the antitumor activity of cryptotanshinone and HDAC inhibitors has been studied extensively, the role of USP21 in antitumor activity remains unclear ( Ashrafizadeh et al, 2021 ; Ruzic et al, 2022 ). In summary, highly potent and specific inhibitors targeting USP21 urgently need to be discovered and developed, which may serve as promising agents for the treatment of multiple forms of cancer and other diseases.…”