Abstract 3801: p53 acetylation by green tea polyphenols leads to upregulation of GSTP1 activity

Abstract

Abstract Epigenetic modifications including DNA methylation and post-translational changes in histone proteins cause alteration in gene regulation. Expression of glutathione-S-transferase Pi (GSTP1), an enzyme of phase II cellular metabolism involved in detoxification of carcinogens and other cellular functions found to be silenced in 80-90% prostate cancers due to hypermethylation of its promoter. We have recently demonstrated that green tea polyphenols (GTPs) cause re-expression of GSTP1 in human prostate cancer LNCaP cells [Int J Cancer. 2009; PMID: 19856314]. However, the mechanism of GSTP1 re-expression is not fully elucidated. Similar to GSTP1 gene, p53 tumor suppressor is also involved in a number of important cellular events including cell cycle, DNA repair, and apoptosis which is reported to be mutated or has defective signaling in most human cancers including prostate cancer. Human GSTP1 gene has a p53-binding motif located in intron 4 and is highly homologous to consensus p53-binding motifs in other p53-responsive genes having the ability to transcriptionally activate GSTP1. Whether p53 participates in GTP-mediated re-expression of GSTP1 is unknown. In the present study we attempted to elucidate the role of tumor suppressor p53 in GSTP1 re-expression after treatment with GTPs. Human prostate cancer LNCaP cells which possess epigenetic signatures of GSTP1 silencing and functional p53 were treated with physiologically achievable doses of GTPs (5μg/mL) or its major constituent epigallocatechin-3-gallate (20μM) up to 7 days. Exposure of LNCaP cells to green tea polyphenols caused acetylation of p53 at its C-terminal amino acid positions K373 and K382, other than K305, which correlated with increased GSTP1 expression. Discontinuation of treatment with GTPs resulted in the loss of p53 acetylation with progressive decrease in GSTP1 expression in these cells. Furthermore, GSTP1 levels were significantly reduced after GTP treatment in cells with the knockdown of p53 expression achieved using shRNA in lentiviral vector. Taken together, our results demonstrate that expression of GSTP1, in part, could be enhanced through p53 acetylation after treatment with green tea polyphenols and thus protect the cells from undergoing epigenetic alterations which may contribute to prostate tumorigenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3801.