ARID2 Loss Destabilizes PBAF and Drives Colorectal Cancer

Three biochemically distinct BRG1 associated factor (BAF) complexes namely canonical (cBAF), poly-bromo (PBAF), and non-canonical (ncBAF) are defined in humans. ARID-domain containing BAF components namely ARID1A, ARID1B (both for cBAF), and ARID2 (for PBAF) define the respective complex assemblies. We previously proposed ARID2's role as a bonafide tumor suppressor in colorectal cancer (CRC), but it's essentiality in maintaining PBAF integrity in CRC remained unexplored. Here, we generated ARID2 knockout HCT116 CRC cells and validated loss of tumor suppression using several cellular and nude mice xenograft assays. Notably, loss of ARID2 led to a marked reduction in PBAF complex assembly, resulting from destabilization of PBAF-specific components BRD7, PHF10, and PBRM1, while core BAF (SMARCD1 and BAF155), ATPase (BRG1), and cBAF (ARID1A) components remained unaffected. Reintroduction of wild-type ARID2 restored PBAF integrity and component levels and reversed the tumorigenic phenotype. Destabilization of PBAF-specific components was also detected upon ARID2 knockdown in HT-29 and SW620 CRC cells. RNA-seq analysis of ARID2 knockout and knockdown CRC cells revealed widespread transcriptional changes affecting disease processes, including CRC and neurodegenerative disorders, as well as cell signaling pathways known to drive CRC, including Wnt/β-catenin, TNFA/NF-κB, and IL2/STAT5; but transcript levels of PBAF-specific components remained unchanged. These results were validated by RT-qPCR. Further, analysis of TCGA RNA-Seq data revealed no significant correlation between transcript levels of ARID2 and other PBAF components. Overall, our study establishes ARID2 as a critical stabilizer of the PBAF complex thus maintaining tumor suppression in CRC.