Ubiquitin-specific peptidase 2a (USP2a) deubiquitinates and stabilizes β-catenin

초록

beta-catenin is not only a key component of adherens junctions but also a transcriptional co-activator downstream of canonical Wnt signaling. The Wnt/beta-catenin pathway plays critical roles in animal development and tissue homeostasis, while mutation or overexpression of beta-catenin often leads to tumorigenesis and metastasis. Ubiquitination-mediated proteasomal degradation of beta-catenin is a key molecular event in the Wnt/beta-catenin pathway. Because deubiquitination of beta-catenin can stabilize beta-catenin and activate Wnt/beta-catenin signaling, targeting the beta-catenin deubiquitinase may provide a strategy for treating beta-catenin-driven cancers. Here, by screening a human deubiquitinase library, we identified USP2a as a deubiquitinase that binds, deubiquitinates, and stabilizes beta-catenin protein. USP2a promotes the nuclear accumulation and transcriptional activity of beta-catenin, leading to elevated expression of Wnt/beta-catenin target genes. Importantly, either genetic knockdown or pharmacological inhibition of USP2a leads to beta-catenin destabilization. These findings suggest that USP2a may serve as a therapeutic target for targeting the cancer-promoting protein beta-catenin.

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