Bmi-1 and Skin Cancer Prevention

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* DESCRIPTION (provided by applicant): Histone modification by Polycomb Group (PcG) proteins is an epigenetic mechanism of paramount importance that controls gene expression by modifying chromatin structure to open or close (silence) genes. This system includes two regulatory complexes, PRC2 and PRC1. PRC2 binds to chromatin and deacetylates and then methylates histone H3 at lysine 27. These events are catalyzed by the PRC2 protein Ezh2, a histone methyltransferase. The trimethylated lysine (H3 K27-3M) then serves as a binding site for the Bmi-1 protein of the PRC1 complex which binds to alter chromatin structure and gene expression. Our ongoing studies in cultured human skin cancer cells demonstrate that treatment with the green tea polyphenol, (-)-epigallocatechin-3-gallate (EGCG), reduces expression of the Bmi-1 and Ezh2 PcG proteins. We propose that chemopreventive agents reduce PcG protein level and activity leading to reduced cell survival. The parent grant focuses on human skin cancer cell lines and a murine skin carcinogenesis models. However, the primary target of carcinogen and chemopreventive agent action is normal human epidermis. Thus, this competitive revision proposal adds a physiological model of human epidermis to our experiments. This new direction will greatly facilitate study of the interplay between EGCG, PcG protein function and response to UVB challenge. The goal of this Competitive Supplement is to examine whether EGCG modulates PcG protein function to attenuate the impact of UVB irradiation using an "epidermal raft culture" system that mimics in vivo skin cell differentiation, and can be engrafted onto mouse dermis as a model to study in vivo behavior of human skin. These models mimic normal human skin biology. These studies significantly extend and expand the power and scope of our study. We argue that these studies are appropriate based on our progress on the parent grant. We hypothesize that Bmi-1 and Ezh2 PcG proteins enhance keratinocyte survival and protect against challenge with UVB or chemopreventive agent and that down-regulation of these proteins by EGCG protects against UVB-dependent cancer. These studies will provide important insights regarding the role of EGCG in cancer prevention using preclinical in vivo models of human epidermal differentiation.