Nutrigenomics and Proteomics in Health and Disease: Towards a Systems-Level Understanding of Gene–Diet Interactions by Martin Kussmann & Patrick J. Stover

Author:Martin Kussmann & Patrick J. Stover [Kussmann, Martin & Stover, Patrick J.]
Language: eng
Format: epub
ISBN: 9781119101260
Publisher: Wiley
Published: 2017-04-17T00:00:00+00:00

7.7 Epigenomic events induced by resveratrol in cancer

Epigenetics refers to heritable changes in gene expression that do not involve changes to the underlying DNA sequence. One of the principal molecular mechanisms associated with epigenetic regulation is the methylation of cysteine residues at specific positions in the DNA. Post‐translational modifications of histones, chromatin remodeling, and non‐coding RNA interfering pathways are also considered as epigenetic mechanisms (Mattick et al., 2009). Epigenomics, which is the study of the complete set of epigenetic modifications on the genetic material of a cell, provides relevant data to decipher and understand the biological mechanisms of carcinogenesis. In particular, the analysis of epigenome data represents a powerful approach for identifying new resveratrol targets. However, the effect of resveratrol on epigenetic regulation is still poorly studied.

It is known that resveratrol alters chromatin conformation by acting directly or indirectly on sirtuin 1 and 2, two members of the histone deacetylase (HDAC) family (Han et al., 2008). Moreover, it promotes acetylation of p53, which increases the expression of p53 target genes that participate in cell death and growth arrest (Zhang et al., 2004). Epigenetic study of prostate cancer (PCa) cell lines DU145 and LNCaP showed for the first time that the accumulation of acetylated p53 results from the inhibitory effect of resveratrol on MTA1 protein, a key component of repressive chromatin implicated in cancer progression and metastasis (Kai et al., 2010). As a result, the destabilization of MTA1–nucleosome remodeling deacetylation (NuRD) co‐repressor complex promotes the accumulation of acetylated p53 and pro‐apoptotic proteins. The identification of MTA1 as a new molecular target of resveratrol also indicated that the combined use of resveratrol with HDAC inhibitors could represent an innovative therapeutic strategy for the treatment of PCa.

In silico docking studies confirmed that resveratrol potentially inhibits the activity of different human HDAC enzymes of class I and II. In agreement, in vitro gene expression assays showed that resveratrol acts an inhibitor of 11 HDACs of class I, II, and IV in a dose‐dependent fashion in HeLa cells. Interestingly, resveratrol induces overall hyperacetylation in human hepatoma HepG2 cells; in particular, it promotes the hyperacetylation of histone protein H3 as a result of HDAC inhibition, which triggers a delayed antiproliferative response and a reduction in cell viability within the first 24 h (Venturelli et al., 2013).

Download

Copyright Disclaimer:
This site does not store any files on its server. We only index and link to content provided by other sites. Please contact the content providers to delete copyright contents if any and email us, we'll remove relevant links or contents immediately.