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

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