Nature communications · 2025
EZH2 loss promotes gastric squamous cell carcinoma.
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Zhang Mengsha, Zhong Ailing, Liu Hongyu, Zhao Lei, Wang Yingjie, Lu Zhenghao, Zhang Lanxin, Pan Xiangyu, Liang Zuoyu, Gao Limin, Chen Xuelan, Wang Jian, Dai Siqi, Wan Xudong, Wang Manli, Chen Jingyao, Du Jiajia, Chen Shuang, Peng Tingfa, Cai Jingyang, Chen Liuxiang, Yang Yang, Xiao Chaoxin, Yao Menglin, Xu Jing, Qin Runkuan, Yang Chan, Wu Baohong, Zhang Qi, Liu Shengzhuo, Zhao Chengjian, Deng Hongxin, Wang Yuan, Chen Lu, Hu Jiankun, Hu Bing, Yang Shengyong, Na Feifei, Guo Linjie, Liu Yu, Chen Chong
Аннотация
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.