EZH2 Mediated Metabolic Rewiring Promotes High-grade Serous Ovarian Cancer Progression Independently of Histone Methyltransferase Activity II

Enhancer of zeste homolog 2 (EZH2), the key catalytic subunit of polycomb repressive complex 2 (PRC2), is overexpressed and exerts an oncogenic role in various cancers through catalytic-dependent or -independent pathways. However, the mechanisms contributing to high-grade serous ovarian cancer (HGSOC) are not well understood. Here, we showed that a subgroup of HGSOC patients with high EZH2 expression but low H3K27me3 level exhibited the worst prognosis. We demonstrated that induction of EZH2 degradation but not catalytic inhibition profoundly blocked ovarian cancer cell proliferation and tumorigenicity in vitro and in vivo. We further demonstrated that EZH2 transcriptionally upregulated IDH2 to potentiate metabolic rewiring by enhancing the tricarboxylic acid cycle (TCA cycle), which contributed to the progression of HGSOC. Together, these data reveal a novel oncogenic role of EZH2 in HGSOC, and provide potential therapeutic strategies in HGSOC by targeting EZH2 non-catalytic activity. Chromatin immunoprecipitation DNA-sequencing (ChIP-seq) for EZH2, H3K27me3 and SUZ12 in OVCAR8 cells.