Dual roles of ARID1A in both mucin production and secretion suggest susceptibilities of gastric signet ring cell carcinoma [CUT&Tag]. Dual roles of ARID1A in both mucin production and secretion suggest susceptibilities of gastric signet ring cell carcinoma [CUT&Tag]

Signet ring cell carcinoma (SRCC) is a lethal malignancy with distinctive histologic features, characterized by mucin-enriched vacuoles in the cytoplasm and compressed nuclei. Gastric SRCC is the most common form of SRCC with increasing incidence in recent years. However, the driver genes of SRCC and the molecular mechanisms underlying its unique morphology remain poorly understood. Here, we report that AT-rich interactive domain-containing protein 1A (ARID1A), one of the most frequently mutated genes in SRCC is a bona fide tumor suppressor gene in gastric SRCC. Its loss, together with Trp53 and Pten loss, drove a SRCC in mice. Mechanistically, Arid1a loss upregulates the expressions of mucins mediated by the BRD9-containing ncBAF complex, which would compete with the ARID1A-containing cBAF complex. And Arid1a can directly regulates the expression of Scin, which is responsible for mucins. And inhibition of Brd9 can ameliorate the malignancy of SRCC. Thus, our study revealed dual roles of ARID1A in restraining SRCC by regulating both mucin production and secretion, providing new mechanistic insights and potential therapeutic vulnerabilities for ARID1A-deficient SRCC. Overall design: We analyzed gastric organoids with two genotypes: Trp53−/−; Pten−/− (TP) and Trp53−/−; Pten−/−; Arid1a−/− (TPA). sgRNAs targeting Pten and Arid1a were introduced into Trp53−/−; Cas9-EGFP gastric organoids to generate the corresponding genotypes. TP organoids served as the control group, and an IgG control was included to account for nonspecific background binding. Organoids from each group were collected for downstream CUT&Tag-seq library preparation and comparative differential binding analyses.