Modifications in gene expression through DNA methylation and remodeling of chromatin via histone proteins are believed to be the most important epigenetic changes observed in initiation and development of prostate cancer. One such alteration is silencing of the expression of glutathione S-transferase-pi (GSTP1), a critical enzyme of carcinogen defense, through methylation of deoxycytidine residue in CpG islands in the 5'- regulating region. Loss of GSTP1 function appears to be the characteristic of prostatic intraepithelial neoplasia lesions, throughout to represent prostate cancer precursors. In recent years, green tea has gained considerable interest as a cancer preventive agent and we have recently demonstrated that oral consumption of green tea polyphenols (GTP) at human achievable dose results in significant inhibition of prostate carcinogenesis in transgenic adenocarcinoma of the mouse Prostate (TRAMP) model and importantly lead to increased tumor free and overall survival of these mice (Proc. Natl. Acad. Sci. USA 98: 10350-5, 2001). This study provides rationale that green tea could be developed as complementary and alternative medicine (CAM) for prostate cancer. Extensive laboratory studies in cell culture systems and in limited animal models have further demonstrated that green tea polyphenols afford protective effects from diverse types of carcinogens and induce phase II enzyme activity that could lead to enhanced detoxification process. Importantly, if drinking green tea can restore or compensate the GSTP1 activity in the prostate and can slow down the process of prostate carcinogenesis that may have relevance for prevention and/or treatment of this disease. Since DNA methylation is influenced by the relative activities of DNA methyltransferases (DNMT) and DNA histone deacetylases (HDAC), the innovative idea to be tested in this proposal is that green tea polyphenols has potential to reactivate the expression of GSTP1 by modulating the enzyme activity of DNMT and HDAC in human prostate carcinoma LNCaP and MDA PCa 2b cells. Importantly, the basal levels of these enzymes are two- to three- folds higher than benign prostatic hyperplasia and normal human prostate epithelial cells and contain completely hypermethylated GSTP1 CpG island alleles. Specifically, we will investigate the potential of green tea polyphenols in i) demethylation of the hypermethylated CpG island alleles in the promoter region of GSTP1 gene and its reactivation, ii) modulation of DNMT and HDAC activity and expression, and iii) alteration in the total and acetylated histone H3 and H4 protein expression in LNCaP and MDA PCa 2b cells. Successful completion of this proposal will set a platform to define the role of green tea polyphenols in modulating epigenetic events in prostate cancer that may contribute to the development of green tea as CAM for its use in prostate cancer patients.
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