E3 ubiquitin ligase WWP2 regulates stability of the chromatin remodeler ARID1B

Abstract

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 novel interacting partner of ARID1B. Our results show that using its WW domains, WWP2 interacts with the PPxY motif located at the N-terminus of ARID1B. We further demonstrate that wild-type WWP2, but not its catalytically inactive mutant, regulates ARID1B protein stability through ubiquitination-mediated proteasomal degradation. Interestingly, WWP2 appears to facilitate non-canonical 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 novel mechanism of post-translational regulation of ARID1B, which may have implications in ARID1B-mediated tumor suppression.