The E3 ubiquitin ligase WWP2 regulates the stability and tumor suppressive properties of the chromatin remodeler ARID1B

ARID1B, a key subunit of the SWI/SNF (also known as BAF) chromatin remodeling complex, is characterized as a canonical tumor suppressor across various cancer types. Although the downregulation of ARID1B transcript levels has been observed in many cancers, its regulation at the protein level is comparatively less studied. Here, we identify WWP2, an E3 ubiquitin ligase, as a previously undescribed interaction partner of ARID1B. Our results show that WWP2 interacts with the PPxY motif located at the N terminus of ARID1B through its WW domains. We further demonstrate that wild-type WWP2, but not a catalytically inactive mutant counterpart, regulates ARID1B protein stability through ubiquitination-mediated proteasomal degradation. Interestingly, WWP2 appears to facilitate noncanonical K27- and K29-linked polyubiquitination of ARID1B. Additionally, silencing WWP2 expression results in a decrease in ubiquitination and a subsequent increase in ARID1B protein levels, indicating that WWP2 plays a crucial role in regulating ARID1B stability. Finally, based on several tumorigenic assays performed in cell lines and mouse xenograft models, we show that WWP2 may modulate ARID1B-mediated tumor suppression. Our results therefore highlight a new mechanism of post-translational regulation of ARID1B, which may have implications in ARID1B-mediated tumor suppression.