Validation of EP400 downstream effectors and potential therapeutic targets in Merkel cell carcinoma

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PROJECT SUMMARY The role of Human Oncogenic Viruses in Cancer Research Tumor viruses are widely spread in human population and are reported to cause 20% of human cancers. The DNA Tumor Viruses express viral oncoproteins that can specifically target the central nodes of host cellular networks. Cellular proteins targeted by tumor viruses are often mutated even in non-viral cancers and very likely to be driving factors of tumorigenesis. While cancer research is normally perplexed by tens of thousands of passenger mutations that reside in cancer genomes, compact small DNA tumor viruses have provided advantages for oncologists to focus on a few viral proteins to dissect gene regulatory networks in cancer. James DeCaprio identified Retinoblastoma Protein (RB1) as the first tumor suppressor using simian polyomavirus SV40 together with three other groups. Using this approach with continued success, the DeCaprio laboratory has continued to discover important cellular proteins by identifying SV40 and more recently Merkel cell polyomavirus T antigen associated proteins. Using SV40 Large T antigen, the DeCaprio laboratory identified CUL7, CUL9, GLMN, FBWX8, FAM111A, the mammalian DREAM complex and the MuvB-FoxM1 complex. These novel binding proteins regulate critical cellular processes, and some are involved in human diseases. More recently, the DeCaprio laboratory has focused on Merkel cell polyomavirus (MCPyV) and its contribution to the highly aggressive Merkel cell carcinoma (MCC). Although MCPyV can infect more than 90% of the global population, it typically does not cause any symptoms. However, MCPyV can cause MCC, a disease several times more lethal than melanoma. Given the oncogenic potential of this widespread virus, it is important for us to understand the functions of human polyomavirus viral antigens and their contribution to cancer. Research Specialist’s Activity/Effort: Recently, we gained novel insight into the mechanisms of tumorigenesis in MCC. We discovered that MCPyV small tumor antigen (ST) recruits L-MYC (MYCL) to the EP400 chromatin complex to drive essential oncogenic processes. I will continue to contribute to the success of Dr. DeCaprio’s research program in the following areas: (1) Identify downstream targets of ST-MYCL-EP400 complex that are required in tumorigenesis; (2) Identify therapeutic targets in MCC and test small molecule inhibitors that may inhibit the viability of MCPyV positive MCC; (3) Generate a mouse model of MCC with targeted integration of MCPyV tumor antigens into a mouse safe harbor locus. My roles include both direct scientific contributions as well as specific training of graduate students and technicians in the DeCaprio laboratory.