Abstract 5190: EZH2 epigenetically silences anti-tumor immunity in melanoma via dual histone and DNA methylation

Abstract

Abstract Despite major advances in immuno- and targeted therapies for metastatic melanoma, not all patients respond to such treatments and the development of therapy resistance remain key obstacles. Novel targets are required and the epigenetic modifier EZH2 may represent such a solution. EZH2 methylates histones causing chromatin compaction and silencing of gene expression. Additionally, EZH2 has been shown to interact with DNA methyltransferases (DNMTs). Aberrant EZH2 in cancer results in the silencing of hundreds of tumor suppressor genes that would normally constrain cancer growth, and 26% of patients in the Australian Melanoma Genome Project (AMGP) display such abnormal EZH2. Using ChIP-seq, microarrays and DNA methylation sequencing, we identified a subset of EZH2 target genes that are silenced by both histone and DNA methylation in melanoma. Interestingly many of these genes play a role in the anti-tumor immune response, including RASSF5 and ITGB2 that facilitate lymphocyte infiltration into tumors and correlate with better survival outcomes in melanoma patients when their expression is high. We show that such genes can be significantly up-regulated by combined treatment with inhibitors of both EZH2 and DNMT in melanoma cells in vitro. Our studies suggest that aberrant EZH2 in melanoma drives aggressive disease via suppression of genes that would normally trigger the anti-tumor immune response. The progression of several preclinical, small molecule inhibitors of EZH2 and DNMTs remains promising. Citation Format: Jessamy Tiffen, Dilini Gunatilake, Stuart Gallagher, Peter Hersey. EZH2 epigenetically silences anti-tumor immunity in melanoma via dual histone and DNA methylation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5190.