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Review
. 2022 Jan 16;14(1):209.
doi: 10.3390/pharmaceutics14010209.

Targeting Histone Deacetylases: Opportunities for Cancer Treatment and Chemoprevention

Dusan Ruzic  1 , Nemanja Djoković  1 , Tatjana Srdić-Rajić  2 , Cesar Echeverria  3 , Katarina Nikolic  1 , Juan F Santibanez  4   5
Affiliations
Review

Targeting Histone Deacetylases: Opportunities for Cancer Treatment and Chemoprevention

Dusan Ruzic et al. Pharmaceutics. .

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.

Keywords: HDAC inhibitors; PROTAC; bifunctional inhibitors; cancer; chemoprevention; clinical trials; dietary-derived inhibitors; epigenetic; histone deacetylases.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Overview of acetylation/deacetylation of histone lysine residues. The acetylation of lysine (Lys) residues catalyzed by histone acetyltransferases (HATs) induces decondensed chromatin and transcriptionally active DNA. In contrast, the histone deacetylases (HDACs) remove acetyl (Ac) residues and provoke condensed chromatin and repression of DNA transcription.
Figure 2
Figure 2
The hallmarks of histone deacetylases in cancer biology. HDACs enzymes mediate cancer cell malignancy by promoting cell proliferation, autophagy, DNA-damage repair, and tumor angiogenesis while inhibiting apoptosis. Furthermore, HDACs contribute to the expression of metastatic phenotypes by triggering the epithelial to the mesenchymal transition program. Arrows indicate stimulation, and the bar represents inhibition.
Figure 3
Figure 3
Classical pharmacophore model of histone deacetylases inhibitors. The classical pharmacophore model of HDAC inhibitors (HDACi) considers three motifs and is illustrated with trichostatin A agent: a hydrophobic cap group (green) that participates in the protein recognition and interaction, a hydrocarbon linker (magenta), and a hydrophilic domain that interact with the Zinc cation (Zn2+) at the enzyme active site called Zinc-binding group (ZBG) (yellow).
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