Melanoma remains a leading cause of death from skin diseases due to its propensity to metastasis, and is increasing rapidly in children. Although, melanoma is less common than other types of skin cancers, however, it causes the majority (75%) of skin cancer-related deaths. The average survival of patients with advanced stage of melanoma is less than a year because no effective strategies are available for metastatic melanoma. Since melanoma is a highly malignant cancer, an approach that can inhibit its growth and progression may facilitate the development of an effective strategy for its treatment or prevention. As green tea polyphenols (GTPs) have been shown to have anti-skin carcinogenic effects, we have examined the chemotherapeutic effect of GTPs on the growth of different melanoma cell lines and the molecular mechanisms underlying these effects using an in vitro model. Treatment of melanoma cells (A375 and Hs294t) with GTPs (0, 20, 40 and 60 µg/ml) for 24 and 48 h significantly inhibited histone deacetylase (HDAC) activity, reduced the levels of class 1 HDAC proteins (HDAC 1, 2, 3 and 8) and enhanced histone acetyltransferase (HAT) activity in a dose-dependent manner. These effects of GTPs on melanoma cells were associated with DNA damage, which was evident by Comet assay, and significant reduction in the viability of melanoma cells and induction of cell death. Concomitant treatment of melanoma cells with a proteasome inhibitor, MG132, prevented GTPs-induced degradation of class I HDACs, suggesting that GTPs reduced the levels of HDAC proteins in melanoma cells through proteasomal degradation. Valproic acid, an inhibitor of HDACs, exhibited a similar pattern of reduced viability and induction of death of melanoma cells (A375 and Hs294t). Treatment of A375 and Hs294t cells with GTPs resulted in an alteration of cell cycle regulatory proteins of G0/G1 phase, and that is a decrease in the levels of cyclin D1, D2 and E, and cyclin dependent kinases, CDK2, CDK4 and CDK6 in a dose-dependent manner. Simultaneously, it was also observed that the levels of p21 and p53 proteins were also increased in the cells after the treatment with GTPs, which may have a role in G0/G1 phase arrest and DNA damage. Together, our study provides new insights into the role of class I HDACs in the chemotherapeutic effects of green tea polyphenols on melanoma cells.

Citation Format: Ram Prasad, Santosh K. Katiyar. Green tea polyphenols inhibit the growth and induce death of melanoma cells by initiating DNA damage and inhibition of class I histone deacetylases. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1242. doi:10.1158/1538-7445.AM2014-1242

©2014 American Association for Cancer Research.
2014