Abstract 1591: Green tea polyphenols reactivate silenced tumor suppressor genes, <i>p16INK4</i> <i>a</i> and <i>Cip1/p21</i>, by reducing DNA methylation and increasing histone acetylation in UV-irradiated mouse skin and skin tumors
Authors: Santosh K. Katiyar, Vijayalakshmi Nandakumar
Journal: Cancer Research (2012)

Abstract Overexposure of the human skin to solar ultraviolet (UV) radiation is the major etiologic factor for the development of skin cancers, and UV-induced epigenetic modifications have been implicated in the risk of this disease. Epigenetic alterations can be inherited without changing the DNA sequence and are believed to play a crucial role in carcinogenesis including photocarcinogenesis. Epigenetic inactivation of genes by promoter hypermethylation has been recognized as an important mechanism by which tumor suppressor genes are shut down during development of tumors. For the development of effective chemopreventive agents and appropriate strategies for the prevention of skin cancers, the consideration of their effects on UV-induced epigenetic modifications is important. Earlier, we have shown that administration of green tea polyphenols (GTPs) in drinking water of SKH-1 hairless mice inhibited UVB-induced skin tumor development; however it is unclear how GTPs affect UV-induced epigenetic modifications during the prevention of UV-induced skin carcinogenesis. The present study was designed to investigate whether administration of GTPs in drinking water of mice would reactivate the expression of tumor suppressor genes in UV-exposed skin and skin tumors, if it is so then what is the underlying mechanism? For this purpose, SKH-1 hairless mice were exposed to UVB (180 mJ/cm2) with and without the administration of GTPs (0.2%, w/v) in drinking water of mice three times per week for 24 weeks. At the termination of the experiment, skin tumors and tumor-uninvolved UV-exposed mouse skin biopsies were harvested and subjected to the analysis of epigenetic biomarkers using immunohistochemistry, western blot analysis, enzymatic activity assays and real-time PCR. Our study shows that the administration of GTPs decreased UVB-induced global DNA methylation levels in UVB-exposed skin. GTPs decreased the levels of UVB-enhanced 5-methylcytosine (5-mC), DNA methyltransferase (DNMT) activity, messenger RNA (mRNA) and protein levels of Dnmt1, Dnmt3a and Dnmt3b. GTPs inhibited UVB-induced histone deacetylation (HDAC) activity and increased levels of acetylated lysine 9 on histone H3 and acetylated lysine 5 and 16 on histone H4. Administration of GTPs resulted in reactivation of the mRNA and proteins of UVB-induced silenced tumor suppressor genes, p16INK4a and Cip1/p21. Identical chemopreventive effects of GTPs were found when UVB-induced skin tumors from mice treated with or without GTPs were analyzed for tumor suppressor genes, the levels of Dnmts, and HDAC activity, etc. Together, these data provide insight into the epigenetic mechanism of action of GTPs against UV radiation effects that may contribute to the chemoprevention of photocarcinogenesis and may have important implications for epigenetic therapy. 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 1591. doi:1538-7445.AM2012-1591