Resveratrol enhances p53 acetylation and apoptosis in prostate cancer by inhibiting MTA1/NuRD complex
Open Access
- 28 January 2010
- journal article
- carcinogenesis
- Published by Wiley in International Journal of Cancer
- Vol. 126 (7), 1538-1548
- https://doi.org/10.1002/ijc.24928
Abstract
Dietary compounds and epigenetic influences are well recognized factors in cancer progression. Resveratrol (Res), a dietary compound from grapes, has anticancer properties; however, its epigenetic effects are understudied. Metastasis-associated protein 1 (MTA1) is a part of the nucleosome remodeling deacetylation (NuRD) corepressor complex that mediates posttranslational modifications of histones and nonhistone proteins resulting in transcriptional repression. MTA1 overexpression in prostate cancer (PCa) correlates with tumor aggressiveness and metastasis. In this study, we have identified a novel MTA1-mediated mechanism, by which Res restores p53-signaling pathways in PCa cells. We show, for the first time, that Res causes down-regulation of MTA1 protein, leading to destabilization of MTA1/NuRD thus allowing acetylation/activation of p53. We demonstrated that MTA1 decrease by Res was concomitant with accumulation of Ac-p53. MTA1 knockdown further sensitized PCa cells to Res-dependent p53 acetylation and recruitment to the p21 and Bax promoters. Furthermore, MTA1 silencing maximized the levels of Res-induced apoptosis and pro-apoptotic Bax accumulation. HDAC inhibitor SAHA, like MTA1 silencing, increased Res-dependent p53 acetylation and showed cooperative effect on apoptosis. Our results indicate a novel epigenetic mechanism that contributes to Res anticancer activities: the inhibition of MTA1/NuRD complexes due to MTA1 decrease, which suppresses its deacetylation function and allows p53 acetylation and subsequent activation of pro-apoptotic genes. Our study identifies MTA1 as a new molecular target of Res that may have important clinical applications for PCa chemoprevention and therapy, and points to the combination of Res with HDAC inhibitors as an innovative therapeutic strategy for the treatment of PCa.Keywords
This publication has 70 references indexed in Scilit:
- Genome-Wide Profiling of Histone H3 Lysine 4 and Lysine 27 Trimethylation Reveals an Epigenetic Signature in Prostate CarcinogenesisPLOS ONE, 2009
- Acetylation of Sirt2 by p300 attenuates its deacetylase activityBiochemical and Biophysical Research Communications, 2008
- Take a break--resveratrol in action on DNACarcinogenesis: Integrative Cancer Research, 2008
- Non-genomic action of resveratrol on androgen and oestrogen receptors in prostate cancer: modulation of the phosphoinositide 3-kinase pathwayBritish Journal of Cancer, 2007
- Dietary histone deacetylase inhibitors: From cells to mice to manSeminars in Cancer Biology, 2007
- Identification of proteins within the nuclear factor-κ B transcriptional complex including estrogen receptor-αAmerican Journal of Obstetrics and Gynecology, 2007
- CLINICAL DEVELOPMENT OF HISTONE DEACETYLASE INHIBITORS AS ANTICANCER AGENTSAnnual Review of Pharmacology and Toxicology, 2005
- Targeting the p53–MDM2 interaction to treat cancerBritish Journal of Cancer, 2004
- Oestrogen inhibits resveratrol-induced post-translational modification of p53 and apoptosis in breast cancer cellsBritish Journal of Cancer, 2004
- Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT MethodMethods, 2001