Deciphering the regulatory mechanisms and biological implications of ARID1A missense mutations in cancer

• Published in: Cell reports (Cambridge) 2024-11, Vol.43 (11), p.114916, Article 114916
• Main Authors: Liu, Fang, Ying, Jun, Yang, Kai, Xiong, Xinyuan, Yang, Nan, Wang, Shu, Zhao, Wenzhen, Zhu, Huiqin, Yu, Ming, Wu, Jun, Yang, Jie, Wang, Xiaonan, Sun, Xuxu
• Format: Article
• Language: English
• Subjects: Animals; ARID1A; cancer; Cell Line, Tumor; Cell Nucleus - metabolism; Chromatin Assembly and Disassembly - genetics; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Exportin 1 Protein; Gene Expression Regulation, Neoplastic; Humans; Karyopherins - genetics; Karyopherins - metabolism; Mice; Mice, Nude; missense mutation; Mutation, Missense - genetics; Neoplasms - genetics; Neoplasms - pathology; STUB1; SWI/SNF complex; Transcription Factors - genetics; Transcription Factors - metabolism; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Ubiquitination
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2024.114916

ARID1A is a key component of the switch/sucrose non-fermentable (SWI/SNF) chromatin remodeling complex and functions as a critical tumor suppressor in various cancers. In this study, we find that tumor cells with hotspot missense mutations in ARID1A (AT-rich interactive domain-containing protein 1A) exhibit a malignant phenotype. Mechanistically, these mutations facilitate the translocation of ARID1A mutant proteins to the cytoplasm by the nucleocytoplasmic shuttler XPO1 (exportin 1). Subsequently, the E3 ubiquitin ligase STUB1 ubiquitinates the ARID1A mutant protein, marking it for degradation. Knocking down STUB1 or inhibiting XPO1 stabilizes the ARID1A mutant protein, retaining it in the nucleus, which restores the assembly of the cBAF complex, the chromatin remodeling function, and the normal expression of genes related to the MAPK and anti-apoptotic pathways, thereby decreasing the tumor burden. Our research shows that nuclear-localized mutated ARID1A proteins retain tumor-suppressive function. We identify promising strategies to treat cancers harboring missense mutations in the BAF complex. [Display omitted] •ARID1A C-terminal hotspot mutants bind XPO1, leading to cytoplasmic translocation•In the cytoplasm, mutant ARID1A proteins are ubiquitinated by STUB1 and degraded•Reduced nuclear ARID1A diminishes SWI/SNF assembly•Targeting XPO1 or STUB1 restores nuclear ARID1A and reduces tumor burden Liu et al. show the mechanism of ARID1A hotspot missense mutant protein translocation and degradation, contributing to tumor progression. Targeting these processes to stabilize mutant ARID1A in the nucleus could restore SWI/SNF assembly and tumor-suppressive function across various cancer types.