Abstract 5584: Green tea polyphenols inhibit histone deacetylases and modulate p53 transcriptional activities in human prostate cancer cells

Abstract

Abstract Inhibitors of histone deacetylases (HDACs) are emerging as a promising class of anticancer drugs. HDAC inhibitors have been demonstrated to induce cellular activities similar to p53-mediated responses such as induction of cell cycle arrest and apoptosis in various malignant cells. Green tea polyphenols (GTP) have shown protective effects against development and progression of various human cancers. GTP-mediated cellular responses include p53 activation, cell cycle arrest and induction of apoptosis in cancer cells. In the present study, we sought to determine whether GTP-mediated cellular responses are similar to that elicited by HDAC inhibitors. For these studies, we used human prostate cancer LNCaP cells, possessing wild-type p53, infected with short hairpin (sh) RNA vector and sh-p53 RNA vector to generate isogenic cell lines. Knockdown of p53 in LNCaP cells caused an increase in the activity of class I HDACs with specific increase in the protein expression of HDAC viz. 1 and 8, respectively. Treatment of both cell lines with 20, 40 and 80 mcg/mL doses of GTP for 24 h resulted in dose-dependent decrease in the total HDAC activity and protein expression of HDAC 2, 3 and 8 and HDAC 1, albeit at highest GTP dose. Similar dose-dependent responses were achieved by trichostatin A (TSA), a well known pharmacological inhibitor of class I and II HDACs in these cells. Interestingly, chemosensitization by GTP was more pronounced in the cells expressing p53 than the isogenic cell lines lacking p53 as observed by cell cycle analysis and annexin V flow cytometric analysis. Furthermore, GTP treatment resulted in marked increase in acetylation of p53 at its C-terminal amino acid positions K373 and K382, other than K305 along with increase in the acetylated forms of histone H3 and H4 which correlated with increased p53 expression, cell cycle arrest and apoptosis. Taken together, these results suggest that interaction of HDACs with p53 probably results in p53 deacetylation, thereby reducing the transcriptional activity; whereas GTP has the ability to cause deacetylation of p53 by reducing the levels of class I HDACs. This seems likely to be, in part, the mechanism for GTP-mediated p53 activation, a similar response elicited by HDAC inhibitors, which are developed as a promising class of drugs for the treatment of various human malignancies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5584. doi:10.1158/1538-7445.AM2011-5584