EZH2缺失促进胃鳞状细胞癌。

EZH2 loss promotes gastric squamous cell carcinoma.

作者信息

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

机构信息

State Key Laboratory of Biotherapy and Cancer Center and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China.

Department of Gastrointestinal Surgery and Laboratory of Gastric Cancer, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China.

出版信息

Nat Commun. 2025 Jul 1;16(1):6032. doi: 10.1038/s41467-025-61024-5.

DOI:10.1038/s41467-025-61024-5

PMID:40595652

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.

摘要

胃鳞状细胞癌（GSCC）是一种罕见但侵袭性强的胃癌亚型，具有独特的组织病理学特征，其病因仍知之甚少。在此，我们对20例GSCC样本进行了基因组分析，发现表观遗传调控基因是最常发生突变的基因之一，包括zeste同源物2增强子（EZH2）。Ezh2缺失在体外胃类器官和体内小鼠模型中均诱导鳞状特征。Ezh2缺陷与Trp53和Pten缺失一起，这两者在GSCC中也经常发生突变，可在小鼠中引发成熟的GSCC。从机制上讲，我们发现Ezh2可通过H3K27甲基化抑制转录因子AP-2γ（Tfap2c）的表达，Tfap2c是一种具有启动表皮鳞状分化能力的转录因子。Tfap2c的破坏降低了Ezh2缺失驱动的GSCC的鳞状特征，并逆转了其对化疗的耐药性。我们的研究结果阐明了GSCC发病机制的关键分子机制，并确定了这种侵袭性恶性肿瘤的潜在治疗靶点。