Stat3 co-operates with mutantEzh2^Y641Fto regulate gene expression and limit the anti-tumor immune response in melanoma

One of the most frequently genetically altered chromatin modifiers in melanoma is the Enhancer of Zeste Homolog 2 (EZH2), the catalytic component of the Polycomb Repressive Complex 2 (PRC2), which methylates lysine 27 on histone 3 (H3K27me3), a chromatin mark associated with transcriptional repression. Genetic alterations inEZH2in melanoma include amplifications and activating point mutations at tyrosine 641 (Y641). The oncogenic role of EZH2 in melanoma has previously been identified; however, its downstream mechanisms remain underexplored. We found that in genetically engineered mouse models,Ezh2Y641Fexpression causes upregulation of a subset of interferon-regulated genes in melanoma cells, suggesting a potential role of the immune system in the pathogenesis of these mutations. Upregulation of these interferon genes was not a result of changes in H3K27me3, but through a direct and non-canonical interaction between Ezh2 and Signal Transducer and Activator of Transcription 3 (Stat3). Ezh2 directly binds Stat3, and, in the presence of Ezh2Y641F, Stat3 protein is hypermethylated. Expression of Stat3 was required to maintain an anti-tumor immune response and its depletion resulted in faster melanoma progression and disease recurrence. Molecularly, Stat3 and Ezh2 bind together at many genomic loci, and can both activate and repress gene expression in association with the rest of the PRC2 complex. These results suggest that Ezh2 can mediate melanomagenesis through evasion of the anti-tumor immune response, and that the immunomodulatory properties of Stat3 are context dependent.