EZH2 mediated metabolic rewiring promotes tumor growth independently of histone methyltransferase activity in ovarian cancer.
EZH2 mediated metabolic rewiring promotes tumor growth independently of histone methyltransferase activity in ovarian cancer.
复制标题
DOI：
10.1186/s12943-023-01786-y
复制
发表时间：
2023-05-20
期刊：
影响因子：
37.3
通讯作者：
Tan, Jing
中科院分区：
文献类型：
--
作者：
Chen, Jianfeng;Hong, Jing Han;Huang, Yulin;Liu, Shini;Yin, Jiaxin;Deng, Peng;Sun, Yichen;Yu, Zhaoliang;Zeng, Xian;Xiao, Rong;Chan, Jason Yongsheng;Guan, Peiyong;Wang, Yali;Wang, Peili;Liu, Lizhen;Wen, Shijun;Yu, Qiang;Ong, Choon Kiat;Teh, Bin-Tean;Xiong, Ying;Tan, Jing
ZAST同源增强子2(EZH2)是多梳抑制复合体2(PRC2)的关键催化亚基，其在多种肿瘤中过表达，并通过催化依赖或非催化途径发挥致癌作用。然而，导致卵巢癌(OC)的相关机制尚不清楚。采用免疫组织化学(IHC)法检测105例卵巢癌组织中EZH2和H3K27me3的表达水平，并对其进行分层。通过染色质免疫沉淀测序(ChIP-Seq)确定EZH2的正则和非正则结合位点。通过对ChIP-Seq和RNA测序数据的综合分析，获得了EZH2单靶基因。体外和体内实验确定EZH2在OC生长中的作用。我们发现，EZH2高表达但H3K27me3低表达的OC患者的预后最差，治疗选择有限。我们证明，在体外和体内，EZH2降解的诱导而不是催化抑制深刻地阻止了OC细胞的增殖和致瘤性。对全基因组染色质和转录组图谱的综合分析表明，EZH2不仅在由H3K27me3标记的基因组座位上广泛占据，而且在与PrC2无关的启动子上也有广泛的占据，表明EZH2在OC中具有非典型性作用。在机制上，EZH2转录上调IDH2，通过增强三羧酸循环(TCA循环)的活性来加强代谢重连，从而促进OC的生长。这些数据揭示了EZH2在OC中的一个新的致癌作用，并通过靶向EZH2的非催化活性来确定OC的潜在治疗策略。网上版载有补充材料，可在10.1186/s12943-023-01786-y查阅。
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. The online version contains supplementary material available at 10.1186/s12943-023-01786-y.
登录
查看更多内容
影响因子：
8
作者：
Chapman-Rothe, N.;Curry, E.;Brown, R.
通讯作者：
Brown, R.
影响因子：
3.2
作者：
Kurmasheva RT;Sammons M;Favours E;Wu J;Kurmashev D;Cosmopoulos K;Keilhack H;Klaus CR;Houghton PJ;Smith MA
通讯作者：
Smith MA
DOI：
10.1158/1541-7786.mcr-10-0398
发表时间：
2010-12
期刊：
Molecular cancer research : MCR
影响因子：
--
作者：
Li H;Cai Q;Godwin AK;Zhang R
通讯作者：
Zhang R
影响因子：
5.7
作者：
Jones BA;Varambally S;Arend RC
通讯作者：
Arend RC
影响因子：
16
作者：
Lee, Shuet Theng;Li, Zhimei;Yu, Qiang
通讯作者：
Yu, Qiang