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Review
. 2020 Jun 23;12(6):1664.
doi: 10.3390/cancers12061664.

Roles of Histone Deacetylases and Inhibitors in Anticancer Therapy

Flávia Alves Verza  1 , Umashankar Das  2 , Ana Lúcia Fachin  1   3 , Jonathan R Dimmock  2 , Mozart Marins  1   2   3   4
Affiliations
Review

Roles of Histone Deacetylases and Inhibitors in Anticancer Therapy

Flávia Alves Verza et al. Cancers (Basel). .

Abstract

Histones are the main structural proteins of eukaryotic chromatin. Histone acetylation/ deacetylation are the epigenetic mechanisms of the regulation of gene expression and are catalyzed by histone acetyltransferases (HAT) and histone deacetylases (HDAC). These epigenetic alterations of DNA structure influence the action of transcription factors which can induce or repress gene transcription. The HATs catalyze acetylation and the events related to gene transcription and are also responsible for transporting newly synthesized histones from the cytoplasm to the nucleus. The activity of HDACs is mainly involved in silencing gene expression and according to their specialized functions are divided into classes I, II, III and IV. The disturbance of the expression and mutations of HDAC genes causes the aberrant transcription of key genes regulating important cancer pathways such as cell proliferation, cell-cycle regulation and apoptosis. In view of their role in cancer pathways, HDACs are considered promising therapeutic targets and the development of HDAC inhibitors is a hot topic in the search for new anticancer drugs. The present review will focus on HDACs I, II and IV, the best known inhibitors and potential alternative inhibitors derived from natural and synthetic products which can be used to influence HDAC activity and the development of new cancer therapies.

Keywords: cancer; chalcones; curcumin; histone acetyltransferase; histone deacetylase inhibitors; histone deacetylases; histones.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Modifications in the structure of histones mediated by histone acetyltransferase (HAT) and histone deacetylase (HDAC). The figure shows the lysine residue undergoing acetylation (HAT) and deacetylation (HDAC).
Figure 2
Figure 2
Schematic organization of the HDAC classes I, II and IV showing the Zn2+-dependent catalytic domains in blue, the NAD+-dependent catalytic domains in pink, the nuclear localization in yellow and the ubiquitin-binding domain of HDAC6 in orange.
Figure 3
Figure 3
Structure of class I HDAC co-repressor Complexes. HDAC1 and HDAC2 are recruited to the (A) SIN3 and the (B) NuRD. Adapted from [96,100,115].
Figure 4
Figure 4
Some non-histone proteins affected by histone deacetylases (HDACs) and the changes caused by these interactions.
Figure 5
Figure 5
Some pathways that are altered by the activity of histone deacetylases. Acetylation and deacetylation of histones alter the chromatin activity, causing important epigenetic changes. In addition, the activity of non-histone proteins is altered, including transcription factors, chaperones and structural proteins, influencing the activity of the different pathways involved in the cell cycle control, apoptosis, differentiation, angiogenesis and cell invasion.
Figure 6
Figure 6
Structures of vorinostat (i), trichostatin A (ii), entinostat (iii) and valproic acid (iv).
Figure 7
Figure 7
Structures of calebin A (i) and ferulic acid (ii).
See this image and copyright information in PMC

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