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

Despite EZH2 is overexpressed and exerts an oncogenic role in various cancer through catalytic-dependent or -independent manner, the mechanisms of EZH2 contributing to high-grade serous ovarian cancer (HGSOC) are incompletely understood. Here, we showed that a subgroup of HGSOC patients with high EZH2 expression but low H3K27me3 level exhibited worst prognosis. We demonstrated that EZH2 degradation but not catalytic inhibition profoundly lowered EZH2 protein and blocked cell proliferation and tumorigenicity in vitro and in vivo. Ectopic expression of EZH2 without SET domain (EZH2-?SET), which is known to be essential for catalytic activity, restored the phenotypes of EZH2 degradation. Mechanistically, we identified that IDH2 was transactivated by EZH2 to impair metabolic rewiring by disrupting the TCA cycle, which contributed to the oncogenic role of EZH2 in OC. Together, these data reveal a novel carcinogenic role of EZH2 in HGSOC, and provide potential strategies in HGSOC by targeting EZH2 non-catalytic activity. Overall design: RNA-seq for OVCAR8 treated with DZNep or doxycycline-induced EZH2 silence was performed (duplicate).

尽管增强子zeste同源物2（EZH2）在多种癌症中过表达，并通过催化依赖或非依赖方式发挥致癌作用，但其在高级别浆液性卵巢癌（High-Grade Serous Ovarian Cancer, HGSOC）中的致病机制尚未完全阐明。本研究发现，亚组EZH2高表达但组蛋白H3赖氨酸27三甲基化（H3K27me3）水平较低的HGSOC患者预后最差。我们证实，降解EZH2而非抑制其催化活性，可显著降低EZH2蛋白水平，并在体内外阻断细胞增殖与致瘤性。异位表达缺失SET结构域的EZH2（EZH2-ΔSET，该结构域对催化活性至关重要），可恢复EZH2降解所引发的表型改变。机制层面，我们发现EZH2可反式激活异柠檬酸脱氢酶2（IDH2），通过破坏三羧酸循环（TCA cycle）干扰代谢重编程，从而介导EZH2在卵巢癌中的致癌作用。综上，本研究揭示了EZH2在HGSOC中的新型致癌功能，并为靶向EZH2非催化活性的HGSOC治疗策略提供了潜在方向。整体实验设计：对经DZNep处理或多西环素诱导EZH2沉默的OVCAR8细胞进行RNA测序（RNA-seq），设置两个生物学重复。