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<p>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 (<i>EZH2</i>). <i>Ezh2</i> loss induces squamous feature both in gastric organoids in vitro and in vivo mouse model. <i>Ezh2</i> deficiency, together with <i>Trp53</i> and <i>Pten</i> loss, both of which are also frequently mutated in GSCC, give rise to full-blown GSCC in mice. Mechanistically, we find that <i>Ezh2</i> could repress the expression of Transcription factor AP-2 gamma (<i>Tfap2c</i>), a transcription factor with the ability to initiate epidermal squamous differentiation, through H3K27 methylation. Disruption of <i>Tfap2c</i> reduces the squamous characteristics of the <i>Ezh2</i> 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.</p>

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EZH2 loss promotes gastric squamous cell carcinoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月1日

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  • 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,
  • Chong Chen

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.