Abstract 4600: Green tea polyphenols causes cell cycle arrest and apoptosis of prostate cancer cells by suppressing class I histone deacetylases

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Green Tea polyphenols (GTP) possess anticancer activity and causes cell cycle arrest and apoptosis in a majority of cancer cells however the mechanism(s) involved in this regulation is still unclear. Recent studies from our group [Int J Cancer 126:2520-33, 2010] reported that GTP has ability to alter gene expression by epigenetic modifications including acetylation/deacetylation of histones. Histone acetyltranferases (HATs) and deacetylases (HDACs) enzymes play important role in these modifications. Acetylation relaxes chromatin, making it accessible to transcription factors and increased gene expression. Deacetylation, on the contrary, represses gene expression. HDACs are grouped into 4 classes: class I (HDACs1-3 & 8), class II (HDACs 4-7 and HDACs 9-10), class III (Sirt1-Sirt7) and class IV (HDAC11). Class I HDACs are overexpressed in many cancer types including prostate cancer and their inhibition leads to cell cycle arrest and apoptosis. Since many dietary agents have been reported to cause cell cycle arrest and apoptosis in cancer cells by inhibiting class I HDACs, we propose similar mechanism of action by GTP. Androgen-responsive human prostate cancer LNCaP (harboring WT p53) and androgen-refractory PC-3 (lacking p53) cells were treated with different doses of GTP (10-80µg/ml) for 24h and expression of HDAC1, 2, 3 and 8, p53, p21, Bax and Bcl2 at protein and message levels were determined. Treatment with GTP resulted in dose-dependent decrease in the expression of HDAC 2, 3 and 8 in both prostate cancer cells, but not in HDAC 1, however total HDAC activity was decreased at the highest dose of 80µg/ml GTP. Subsequently, increased acetylation of histone H3 at Lys 9/18 and Histone H4 was observed after GTP treatment. GTP treatment resulted in increased expression of p21and Bax and decrease in Bcl2 at protein and message level in these cells. These alterations were consistent with the G1 phase arrest in dose- and time-dependent manner (69%-80% in LNCaP cells and 40%-62% in PC-3 cells) after GTP treatment. Exposure of cells with GTP up to 72 h resulted in the induction of apoptosis in both cell lines (2.7-84.5% in LNCaP cells and 4.0-85.2% in PC3 cells) as measured by annexin V assay. Furthermore, treatment of cells with proteasomal inhibitor, MG132 together with GTP prevented degradation of class I HDACs, compared to cells treated with GTP alone, indicating increased proteasomal degradation of class I HDACs by GTP. Taken together, we conclude that inhibition of class I HDACs and increased acetylation of histone proteins by GTP contributes to the mechanism of GTP-induced cell cycle arrest and apoptosis of prostate cancer cells, irrespective of their p53 status. 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 4600. doi:10.1158/1538-7445.AM2011-4600