EZH2 loss promotes gastric squamous cell carcinoma
Release date:
2025-05-07
Description:
Gastric Squamous Cell Carcinoma (GSCC) is a rare but aggressive subtype of gastric cancer with unique histopathology, whose etiology is largely unknown. Here, we performed genomics analyses of twenty GSCC samples and found that epigenetic regulation genes were among the most frequently mutated genes, including Enhancer of zeste homolog 2 (EZH2). Ezh2 loss led to squamous feature both in gastric organoids in vitro and in vivo. Ezh2 deficiency, together with Trp53 and Pten loss, both of which were also frequently mutated in GSCC, gave rise to full-blown GSCC in mice. Mechanistically, we found 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 reduced the squamous characteristics of the Ezh2 loss-driven GSCC and reversed its resistance to chemo treatment. Our study revealed the mechanisms of GSCC tumorigenesis and shed light on future treatment.
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Whole-exome sequencing was conducted on tumor regions isolated via laser capture microdissection from formalin-fixed, paraffin-embedded (FFPE) tissue sections derived from 20 cases of gastric squamous cell carcinoma (GSCC).
Organization: West China Hospital, Sichuan University
Submission date: 2025-04-21
Requests: -
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