EZH2 mediated metabolic rewiring promotes tumor growth independently of histone methyltransferase activity in ovarian cancer

Molecular Cancer

Research

Jing Han Hong¹  Qiang Yu²  Peiyong Guan²  Choon Kiat Ong³  Bin-Tean Teh⁴  Lizhen Liu⁵  Zhaoliang Yu⁶  Yichen Sun⁷  Shini Liu⁸  Jason Yongsheng Chan⁹  Rong Xiao^1,10  Yali Wang^1,10  Xian Zeng^1,10  Peng Deng^1,10  Shijun Wen^1,10  Peili Wang^1,10  Ying Xiong^1,10  Yulin Huang^1,10  Jiaxin Yin^1,10  Jianfeng Chen^1,11  Jing Tan^1,12 

[1] Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore, Singapore;Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore, Singapore;Genome Institute of Singapore, A*STAR, Singapore, Singapore;Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore, Singapore;Genome Institute of Singapore, A*STAR, Singapore, Singapore;Lymphoma Genomic Translational Research Laboratory, Cellular and Molecular Research, National Cancer Centre Singapore, Singapore, Singapore;Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore, Singapore;Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore, Singapore;Genome Institute of Singapore, A*STAR, Singapore, Singapore;Center of Medical Research, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, 510060, Guangdong, P. R. China;Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, 510655, Guangzhou, Guangdong, P. R. China;Department of Laboratory Medicine, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, 510060, Guangdong, P. R. China;Department of Oncology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, 510060, Guangdong, P. R. China;Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore, Singapore;State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, 510060, Guangzhou, P. R. China;State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, 510060, Guangzhou, 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, 510060, Guangzhou, Guangdong, P. R. China;State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, 510060, Guangzhou, 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, 510060, Guangzhou, Guangdong, P. R. China;Department of Laboratory Medicine, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, 510060, Guangdong, P. R. China;Center of Medical Research, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, 510060, Guangdong, P. R. China;

关键词: Ovarian cancer;    EZH2;    IDH2;    TCA cycle;    Metabolic rewiring;   

DOI  :  10.1186/s12943-023-01786-y

 received in 2022-11-02, accepted in 2023-05-09,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundEnhancer 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.MethodsThe 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.ResultsWe 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.ConclusionsThese data reveal a novel oncogenic role of EZH2 in OC and identify potential therapeutic strategies for OC by targeting the noncatalytic activity of EZH2.

【 授权许可】

CC BY   
© The Author(s) 2023

【 图 表 】

40517_2023_256_Article_IEq139.gif

Fig. 3

41512_2023_147_Article_IEq110.gif

40517_2023_256_Article_IEq119.gif

Fig. 14

Fig. 4