State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China.
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 East Dongfeng Road, Guangzhou, Guangdong, 510060, P. R. China.
Mol Cancer. 2023 May 20;22(1):85. doi: 10.1186/s12943-023-01786-y.
Enhancer of zeste homolog 2 (EZH2), the key catalytic subunit of polycomb repressive complex 2 (PRC2), is overexpressed and plays an oncogenic role in various cancers through catalysis-dependent or catalysis-independent pathways. However, the related mechanisms contributing to ovarian cancer (OC) are not well understood.
The levels of EZH2 and H3K27me3 were evaluated in 105 OC patients by immunohistochemistry (IHC) staining, and these patients were stratified based on these levels. Canonical and noncanonical binding sites of EZH2 were defined by chromatin immunoprecipitation sequencing (ChIP-Seq). The EZH2 solo targets were obtained by integrative analysis of ChIP-Seq and RNA sequencing data. In vitro and in vivo experiments were performed to determine the role of EZH2 in OC growth.
We showed that a subgroup of OC patients with high EZH2 expression but low H3K27me3 exhibited the worst prognosis, with limited therapeutic options. We demonstrated that induction of EZH2 degradation but not catalytic inhibition profoundly blocked OC cell proliferation and tumorigenicity in vitro and in vivo. Integrative analysis of genome-wide chromatin and transcriptome profiles revealed extensive EZH2 occupancy not only at genomic loci marked by H3K27me3 but also at promoters independent of PRC2, indicating a noncanonical role of EZH2 in OC. Mechanistically, EZH2 transcriptionally upregulated IDH2 to potentiate metabolic rewiring by enhancing tricarboxylic acid cycle (TCA cycle) activity, which contributed to the growth of OC.
These data reveal a novel oncogenic role of EZH2 in OC and identify potential therapeutic strategies for OC by targeting the noncatalytic activity of EZH2.
增强子结合锌指蛋白 2（EZH2）是多梳抑制复合物 2（PRC2）的关键催化亚基，通过依赖催化或非依赖催化的途径在各种癌症中过表达并发挥致癌作用。然而，导致卵巢癌（OC）的相关机制尚不清楚。
通过免疫组织化学（IHC）染色评估 105 例 OC 患者中 EZH2 和 H3K27me3 的水平，并根据这些水平对这些患者进行分层。通过染色质免疫沉淀测序（ChIP-Seq）定义 EZH2 的经典和非经典结合位点。通过整合 ChIP-Seq 和 RNA 测序数据的分析获得 EZH2 独奏靶标。进行体外和体内实验以确定 EZH2 在 OC 生长中的作用。
我们表明，EZH2 高表达但 H3K27me3 低的 OC 患者亚组预后最差，治疗选择有限。我们证明，诱导 EZH2 降解而不是催化抑制在体外和体内深刻地阻断了 OC 细胞的增殖和致瘤性。全基因组染色质和转录组谱的综合分析揭示了 EZH2 不仅在基因组位点上广泛占据 H3K27me3 标记的位置，而且在不依赖 PRC2 的启动子上占据，表明 EZH2 在 OC 中具有非经典作用。从机制上讲，EZH2 转录上调 IDH2 通过增强三羧酸循环（TCA 循环）活性来增强代谢重编程，从而促进 OC 的生长。
这些数据揭示了 EZH2 在 OC 中的新型致癌作用，并通过靶向 EZH2 的非催化活性为 OC 确定了潜在的治疗策略。
