biostudies-literatureUnknown16(1)Zhang MGastric 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 meNature communications6032https://www.ebi.ac.uk/biostudies/studies/S-EPMC12215077biostudies-literatureEZH2 loss promotes gastric squamous cell carcinoma.PMC12215077Liu HZhong APeng TLu ZLiang ZCai JWu BZhang MZhang LWan XLiu SWang JQin RZhang QDeng HWang MLiu YGuo LZhao LChen XWang YChen SNa FPan XZhao CChen JChen LYao MChen CYang CHu BXu JYang YDai SHu JGao LDu JXiao CYang SfalseEZH2 loss promotes gastric squamous cell carcinoma.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 me2025-01-01T00:00:00Z2025 Jul2026-06-01T11:34:08.505Z2026-04-08T11:51:03.873ZS-EPMC122150774059565210.1038/s41467-025-61024-5