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 unique histologic features, characterized with large vacuoles and compressed nuclei. Gastric SRCC is the most common SRCC, and its incidence is increasing recently. However, the driver genes of SRCC and the molecular mechanisms underlying its unusual histology remain unclear. Here, we developed a new type of gastric SRCC mouse models with gene-edited premalignant gastric organoids and validated ARID1A, one of the most frequently mutated genes in SRCC, as a bona fide tumor suppressor gene of gastric SRCC. Mechanistically, through CUT/Tag and ATAC-seq analyses, we found that Arid1a directly regulated the expressions of secretory factors Scin and on the other hand, Arid1a loss reprogrammed the genome binding of the SWI/SNF complexes and increased the expressions of mucin genes through the binding of Brd9, a component of the noncanonical SWI/SNF complex. Inhibiting Brd9 reversed the pathology of Arid1a mutant SRCC. Thus, our studies revealed dual roles of ARID1A in restraining SRCC through both mucin production and secretion. These findings offer new insights into the susceptibilities of ARID1A deficient SRCC.