Deciphering the novel regulatory mechanisms and biological implications of ARID1A C-terminal missense mutations in cancer [RNA-seq]

ARID1A (the AT-rich interaction domain 1A, also known as BAF250a), a pivotal component of the SWI/SNF chromatin remodeling complex, is frequently mutated in various cancers. In this study, we discovered that mutations such as ARID1A V2084D or V2087E lead to the binding of ARID1A mutant with the nucleocytoplasmic shuttling protein XPO1, facilitating ARID1A mutant transport to the cytoplasm. Subsequently, the E3 ubiquitin ligase STUB1 recognizes and ubiquitinates ARID1A mutant protein, marking it for degradation. This reduction in protein levels due to the mutation impedes the assembly of the cBAF complex and the expression of tumor-suppressive target genes, ultimately contributing to a malignant phenotype. Knocked down STUB1 or inhibit XPO1 activity stabilizes the ARID1A mutant protein, retaining it in the nucleus, which restores the assembly of the cBAF complex, chromatin remodeling function, and the expression of critical genes, thereby decrease the tumor burden.