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EZH2 loss promotes gastric squamous cell carcinoma

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收录情况： ◇ 自然指数

作者：
Zhang Mengsha[1] * ; Zhong Ailing[1] * ; Liu Hongyu[1] * ; Zhao Lei[1] * ; Wang Yingjie[1] ; Lu Zhenghao[2] ; Zhang Lanxin[1] ; Pan Xiangyu[1] ; Liang Zuoyu[3] ; Gao Limin[3] ; Chen Xuelan[1] ; Wang Jian[1] ; Dai Siqi[1] ; Wan Xudong[1] ; Wang Manli[1] ; Chen Jingyao[1] ; Du Jiajia[1] ; Chen Shuang[1] ; Peng Tingfa[4] ; Cai Jingyang[5] ; Chen Liuxiang[6] ; Yang Yang[7] ; Xiao Chaoxin[1] ; Yao Menglin[8] ; Xu Jing[9] ; Qin Runkuan[1] ; Yang Chan[3] ; Wu Baohong[1] ; Zhang Qi[1] ; Liu Shengzhuo[10] ; Zhao Chengjian[1] ; Deng Hongxin[1] ; Wang Yuan[1] ; Chen Lu[1] ; Hu Jiankun[2] ; Hu Bing[6] ; Yang Shengyong[1] ; Na Feifei[1] ; Guo Linjie[6] ; Liu Yu[11] ; Chen Chong[1,12] ;
机构： [1]State Key Laboratory of Biotherapy and Cancer Center and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China. [2]Department of Gastrointestinal Surgery and Laboratory of Gastric Cancer, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China. [3]Department of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan, China. [4]Department of Gastroenterology, Armed Police Forces Hospital of Sichuan, Chengdu, Sichuan, China. [5]Department of Electronic Science and Engineering, University of Electronic Science and Technology, Chengdu, Sichuan, China. [6]Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, Sichuan, China. [7]Cancer center, West China hospital of Sichuan University, Guoxue Xiang, Chengdu, China. [8]Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, China. [9]Department of Hematology, West China Hospital, Sichuan University, Chengdu, Sichuan, China. [10]Department of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan, China. [11]Department of Hematology and Institute of Hematology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China. [12]Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu, Sichuan, China.
出处：
DOI： 10.1038/s41467-025-61024-5

摘要：
Gastric Squamous Cell Carcinoma (GSCC) is a rare but aggressive subtype of gastric cancer with unique histopathology, whose etiology remains poorly understood. Here, we perform genomics analyses of twenty GSCC samples and find that epigenetic regulation genes are among the most frequently mutated genes, including Enhancer of zeste homolog 2 (EZH2). Ezh2 loss induces squamous feature both in gastric organoids in vitro and in vivo mouse model. Ezh2 deficiency, together with Trp53 and Pten loss, both of which are also frequently mutated in GSCC, give rise to full-blown GSCC in mice. Mechanistically, we find that Ezh2 could repress the expression of Transcription factor AP-2 gamma (Tfap2c), a transcription factor with the ability to initiate epidermal squamous differentiation, through H3K27 methylation. Disruption of Tfap2c reduces the squamous characteristics of the Ezh2 loss-driven GSCC and reverses its resistance to chemo treatment. Our findings elucidate key molecular mechanisms underlying GSCC pathogenesis and identify potential therapeutic targets for this aggressive malignancy.© 2025. The Author(s).

基金：
This work was supported by grants from the National Natural Science Foundation of China (82330087 [C.C.]; T2221004 [C.C.], 82130007 [Y.L.], 82470188 [Y.L.], 82170171 [C.C.], 82303880 [M.W.], 82300185 [Q.Z.], 82300186, [B.W.]); the National Science and Technology Major Project of China (2023ZD0500500 [Y.L.], 2024YFF0507400 [C.C.]); the Sichuan Science and Technology Program (2025NSFTD0030 [Y.L.], 2023ZYD0057 [Y.L.], 2025ZNSFSC0047 [C.C.]; the Frontiers Medical Center, Tianfu Jincheng Laboratory Foundation (TFJC2023010004 [C.C.]); the 1.3.5. Project for Disciplines of Excellence, West China Hospital, Sichuan University (ZYGD22012 [Y.L.]); National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University (Z2024JC001 [C.C.]); the 1.3.5. Project for Disciplines of Excellence, West China Hospital, Sichuan University (ZYGD22012 [Y.L.]); Chengdu Science and Technology Project (2024-YF05-00535-SN,[J.X.]); Natural Science Foundation of Sichuan Province of China (2024NSFSC1696, [J.X.], 2024NSFSC1699, [B.W.], 2023NSFSC1904 [M.W.]); Postdoctoral Fellowship Programof CPSF (GZB20230466 [Q.Z.]); China Postdoctoral Science Foundation (2023M732465 [Q.Z.]); the Post-Doctor Research Project,West China Hospital, Sichuan University (2023HXBH018 [M.W.], 2023HXBH094 [Q.Z.]); the China Postdoctoral Science Foundation under Grant Number (2023M732457 [B.W.], 2023TQ0226 [B.W.], 2024T170604 [Q.Z.], 2023M732465[Q.Z.]); the Post-Doctor Research Project of Sichuan University (2024SCU12033, [B.W.]).
语种：
外文
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出版当年[2025]版：
大类 | 1 区 综合性期刊
小类 | 1 区 综合性期刊
最新[2025]版：
大类 | 1 区 综合性期刊
小类 | 1 区 综合性期刊
第一作者：
第一作者机构： [1]State Key Laboratory of Biotherapy and Cancer Center and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
共同第一作者：
通讯作者：
通讯机构： [1]State Key Laboratory of Biotherapy and Cancer Center and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China. [12]Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu, Sichuan, China.
推荐引用方式(GB/T 7714)：
Zhang Mengsha,Zhong Ailing,Liu Hongyu,et al.EZH2 loss promotes gastric squamous cell carcinoma[J].Nature Communications.2025,16(1):6032.doi:10.1038/s41467-025-61024-5.
APA：
Zhang Mengsha,Zhong Ailing,Liu Hongyu,Zhao Lei,Wang Yingjie...&Chen Chong.(2025).EZH2 loss promotes gastric squamous cell carcinoma.Nature Communications,16,(1)
MLA：
Zhang Mengsha,et al."EZH2 loss promotes gastric squamous cell carcinoma".Nature Communications 16..1(2025):6032

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