Review Article: EZH2 in Pancreatic Cancer: Epigenetic Driver and Therapeutic Target

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Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers and the poorly responsive to current therapeutics. There is an emergent need to develop new therapies as well as new predictive and prognostic biomarkers. Several mechanisms have been reported in PDAC that underlie the tumor aggressiveness and its highly intrinsic resistance. One factor that has been revealed is the overexpression of the epigenetic enhancer of zeste homolog 2 (EZH2) in PDAC and that plays a central role in its pathogenesis, malignancy, and resistance to conventional therapies and immune evasion. EZH2 is a catalytic component of the polycomb repressive complex 2 (PRC2) that regulates and represses gene expression. EZH2-mediated epigenetic silencing via the trimethylation of lysine 27 of histone H3 (H3K27me3) is also involved in the suppression of tumor suppressors and anti-apoptotic genes and the activation of genes involved in cell cycle progression, cell proliferation, and differentiation. High EZH2 expression in PDAC correlates with lymph node metastases, advanced clinical stage, and is an indicator of poor prognosis. While current treatment with checkpoint inhibitors resulted in significant clinical responses in various cancers, however, it failed in PDAC due to EZH2-induced immune evasion and contribution to a highly immunosuppressive tumor microenvironment (TME). Various EZH2 inhibitors have been developed, but not clinically effective in PDAC. Alternative approaches targeting EZH2 are proposed.