EZH2 loss promotes gastric squamous cell carcinoma

Mengsha Zhang, Ailing Zhong, Hongyu Liu, Lei Zhao, Yingjie Wang, Zhenghao Lu, Lanxin Zhang, Xiangyu Pan, Zuoyu Liang, Limin Gao, Xuelan Chen, Jian Wang, Siqi Dai, Xudong Wan, Manli Wang, Jingyao Chen, Jiajia Du, Shuang Chen, Tingfa Peng, Jingyang Cai, Liuxiang Chen, Yang Yang, Chaoxin Xiao, Menglin Yao, Jing Xu, Runkuan Qin, Chan Yang, Baohong Wu, Qi Zhang, Shengzhuo Liu, Chengjian Zhao, Hongxin Deng, Yuan Wang, Lu Chen, Jiankun Hu, Bing Hu, Shengyong Yang, Feifei Na (), Linjie Guo (), Yu Liu () and Chong Chen ()
Additional contact information
Mengsha Zhang: Sichuan University
Ailing Zhong: Sichuan University
Hongyu Liu: Sichuan University
Lei Zhao: Sichuan University
Yingjie Wang: Sichuan University
Zhenghao Lu: Sichuan University
Lanxin Zhang: Sichuan University
Xiangyu Pan: Sichuan University
Zuoyu Liang: Sichuan University
Limin Gao: Sichuan University
Xuelan Chen: Sichuan University
Jian Wang: Sichuan University
Siqi Dai: Sichuan University
Xudong Wan: Sichuan University
Manli Wang: Sichuan University
Jingyao Chen: Sichuan University
Jiajia Du: Sichuan University
Shuang Chen: Sichuan University
Tingfa Peng: Armed Police Forces Hospital of Sichuan
Jingyang Cai: University of Electronic Science and Technology
Liuxiang Chen: Sichuan University
Yang Yang: Guoxue Xiang
Chaoxin Xiao: Sichuan University
Menglin Yao: Sichuan University
Jing Xu: Sichuan University
Runkuan Qin: Sichuan University
Chan Yang: Sichuan University
Baohong Wu: Sichuan University
Qi Zhang: Sichuan University
Shengzhuo Liu: Sichuan University
Chengjian Zhao: Sichuan University
Hongxin Deng: Sichuan University
Yuan Wang: Sichuan University
Lu Chen: Sichuan University
Jiankun Hu: Sichuan University
Bing Hu: Sichuan University
Shengyong Yang: Sichuan University
Feifei Na: Sichuan University
Linjie Guo: Sichuan University
Yu Liu: Sichuan University
Chong Chen: Sichuan University

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-61024-5

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