Abstract 2583: Green tea polyphenols cause stabilization and increased transcriptional activity of p53 by increasing its acetylation through inhibition of class I histone deacetylases

Abstract

Abstract p53, a major tumor suppressor and transcription factor protects the cells from both internal and external stress by modulating cell cycle and apoptotic pathways. p53 is mutated in more than 50% of human cancer and in most others, its pathway is defective. p53 undergoes a number of posttranslational modifications including acetylation of lysine (Lys) residues on its C-terminal. Acetylation of p53 at Lys373 and Lys382 has been reported to decrease its degradation and increased binding to DNA, leading to increased transcription of its downstream targets such as p21/waf1 and Bax. The process of acetylation is regulated by a group of opposing enzymes histone acetyltransferase (HATs) and histone deacetylases (HDACs). Class I HDACs (HDAC 1, 2, 3 and 8) are shown to be upregulated in a variety of human cancers including prostate cancer and their inhibition by HDAC inhibitors leads to cell cycle arrest and apoptosis in cancer cells. In pursuit of safe and effective HDAC inhibitors, we earlier demonstrated that green tea polyphenols (GTP) and its major constituent, (-) epigallocatechin-3-gallate (EGCG) has ability to inhibit class I HDACs in human prostate cancer cells. Here we demonstrate that GTP and EGCG activates p53 through acetylation at the Lys373 and Lys382 residues by inhibiting class I HDACs in human prostate cancer LNCaP cells. Treatment of cells with GTP (2.5-10μg/ml) and EGCG (5-20μM) resulted in dose and time dependent inhibition of class I HDACs, albeit at varying levels. Discontinuation of treatment with GTP/EGCG resulted in the loss of p53 acetylation at both the sites in these cells. GTP/EGCG treatment also resulted in increased expression of p21/waf1 and Bax at the protein and message levels. The increased GTP/EGCG-mediated p53 acetylation enhanced its binding on the promoters of p21/waf1 and Bax, which was associated with the increase accumulation of cells in the G0/G1 phase of the cell cycle and induction of apoptosis. Taken together, our findings indicate that GTP/EGCG causes acetylation of p53 by inhibiting class I HDACs which is likely to be part of the mechanism that control the physiological activity of p53. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2583. doi:1538-7445.AM2012-2583