EZH2 loss promotes gastric squamous cell carcinoma [CUT&Tag]

Gastric Squamous Cell Carcinoma (GSCC) is a rare subtype of gastric cancer with unique histopathology while gastric adenosquamous carcinoma (GASC), which partially shares features of GSCC, is more frequent. Both GSCC and GASC have poor prognosis but the molecular mechanisms underlying these malignancies are unknown. Here, we performed genomics analyses of eleven GSCC samples and found that epigenetic regulation genes were among the most frequently mutated genes. Among them was Enhancer of zeste homolog 2 (EZH2), which was also significantly downregulated in GASC, compared to gastric adenocarcinoma (GAC). Ezh2 loss led to squamous feature both in gastric organoids in vitro and in vivo. Importantly, 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 reversed Ezh2 loss-driven GSCC into GAC and reduced its resistance to chemo treatment. Our study revealed the mechanisms of GSCC/GASC tumorigenesis and shed light on future treatment.