Dual roles of ARID1A in both mucin production and secretion suggest susceptibilities of gastric signet ring cell carcinoma

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 SRCC in mice. Mechanistically, Arid1a loss upregulates the expression of mucins mediated by the BRD9-containing ncBAF complex, which competes with the ARID1A-containing cBAF complex. In addition, Arid1a directly regulates the expression of Scin, which is responsible for mucin secretion. Inhibition of Brd9 can ameliorate the malignancy of SRCC. Thus, our study reveals 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.