GSE209852
EZH2 Catalytic Inhibition Prevents Urothelial Carcinoma Progression Through Immune Activation [ChIP-seq]
The long-term survival of advanced urothelial carcinoma (UCa) patients is limited due to an innate resistance to treatment. We identified elevated expression of the histone methyltransferase EZH2 as a hallmark of aggressive UCa, and therefore, hypothesized that EPZ-011989, a small molecule catalytic inhibitor of EZH2, might have anti-tumor effects in UCa. Here we show that in a carcinogen-induced mouse bladder cancer model, EZH2 inhibition results in reduced tumor progression, elevated tumor infiltrating T cells, increased pro-inflammatory cytokine secretion and MHC class II expression on UCa cells. Treatment of mice with EPZ011989 causes increased MHC class II expression on the urothelium, and was able to activate CD4+ T cells, which is completely abrogated with genetic ablation of the acquired immune system.  These findings support a unique role for EZH2 catalytic activity in mediating UCa immune evasion and, for the first time, prove the efficacy of EZH2 catalytic inhibitors in a UCa model, a finding that can potentially be expanded to humans with UCa. Overall design: Chromatin immunoprecipitation sequencing (Chip-seq) for histone modification H3K27me3