Merkel cell carcinoma (MCC) is an aggressive skin cancer. In 2008, the integration of the Merkel cell Polyomavirus (MCPyV) and the expression of the two viral oncogenes were identified as main MCC oncogenic triggers. Recently the expression of EZH2 (Enhancer of zest homolog 2), an histone methyl transferase involved in aggressiveness of some solid cancer, was observed in MCC tumors. In this context, our working hypothesis was that EZH2 expression can be virus-driven and could represent a therapeutic target. To confirm this hypothesis, we first evaluated expression of EZH2 and H3K27me3 signature by immunochemistry in a cohort of 147 MCC tumors. This analysis confirmed EZH2 expression in most of the MCC samples (n=125, 74,8%) and revealed higher expression levels in MCPyV-positive tumors than in MCPyV-negative tumors (p=0,022) suggesting a possible induction of EZH2 expression by the viral oncogenes. Moreover, high EZH2 expression levels were associated with poor outcome (recurrence free and specific survivals) suggesting a contribution of EZH2 to MCC aggressiveness. Accordingly, ectopic expression of viral oncogenes in primary fibroblasts induced over-expression of EZH2 in vitro. Moreover, EZH2 inhibition by RNA interference or by chemical inhibitors (Tazemetostat or GSK343) in MCC cell lines induce cell death in vitro (cell cycle analysis and mixed culture assay). Finally, a reduction of tumor growth after exposition to a chemical EZH2 inhibitor (GSK343) was confirmed in vivo in aSCID mice xenograft MCC model. To conclude, overexpression of EZH2 on MCC tumors and its role on MCC aggressiveness suggest the potential of EZH2 as a drug target in MCC.

ESDR250 - EZH2, a potential therapeutic target in Merkel cell carcinoma

50th Annual Meeting of the European Society for Dermatological Research. VIRTUAL MEETING