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March 7th, 2025
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Centre for DNA Fingerprinting and Diagnostics (CDFD)
cancer biology
biorxiv

E3 ubiquitin ligase WWP2 regulates stability of the chromatin remodeler ARID1B

Hore, P.Open in Google Scholar•Bambhaniya, S.Open in Google Scholar•Bashyam, M. D.Open in Google Scholar

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, the regulation of ARID1B at the protein level is comparatively less studied. Here, we identify WWP2, an E3 ubiquitin ligase, as a novel interacting partner of ARID1B. We further show that using its WW domains, WWP2 interacts with the PPxY motif within the N-terminal intrinsically disordered region of ARID1B. The ability of wild-type (but not the catalytically inactive) WWP2 to modulate ARID1B protein stability was confirmed through cycloheximide chase assay. Interestingly, WWP2 appears to facilitate non-canonical K27-linked polyubiquitination of ARID1B, leading to the latters subsequent proteasomal degradation. 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. Based on several tumorigenic assays, we show that WWP2 may modulate ARID1B-mediated tumor suppression. Our results highlight a novel mechanism of post-translational regulation of ARID1B, which may have implications in ARID1B-mediated tumor suppression.

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