Ezh2Y641F mutations co-operate with Stat3 to regulate MHC class I antigen processing and alter the tumor immune response in melanoma

Enhancer of Zeste Homolog 2 (EZH2) is the catalytic component of the Polycomb Repressive Complex 2, a chromatin modifying complex, which mediates methylation of lysine 27 on histone 3 (H3K27me3), a repressive chromatin mark. Genetic alterations in EZH2 in melanoma include amplifications and activating point mutations at tyrosine 641 (Y641) whose underlying oncogenic mechanisms remain largely unknown. Here, we found that expression of EZH2^Y641F causes upregulation of a subset of interferon-regulated genes in melanoma cells. Upregulation of these genes was not a direct effect of changes in H3K27me3, but via a non-canonical interaction between EZH2 and Signal Transducer and Activator of Transcription 3 (STAT3). EZH2 and STAT3 together function as transcriptional activators to mediate gene activation of numerous genes, including MHC Class 1b antigen processing genes. Furthermore, expression of STAT3 is required to maintain an anti-tumor immune response in EZH2^Y641F melanomas and to prevent melanoma progression and recurrence.