Fbxo2 inhibits cell proliferation, migration and invasion by the ubiquitin-mediated degradation of WEE1 in renal cell carcinoma.

Abstract

Background: Fbxo2 is part of the SKP1-Cullin-F-box (SCF) E3 ubiquitin ligase complex. While increasing evidence indicates that Fbxo2 influences tumorigenesis and progression in various human malignancies, its biological importance and molecular mechanisms in renal cell carcinoma (RCC) are poorly understood.

Methods: Bioinformatic analysis of publicly available datasets was utilized to determine the association between Fbxo2 expression and survival in RCC patients. CCK8, colony-formation, and EdU assays were carried out to measure cell proliferation after Fbxo2 modulation in RCC cells. Coimmunoprecipitation, mass spectrometry, Western blotting, and ubiquitin assays were performed to explore the molecular mechanism of Fbxo2-involved tumorigenesis in RCC.

Results: Fbxo2 suppresses RCC cell growth. Moreover, higher Fbxo2 expression was positively associated with improved overall survival in RCC patients. In RCC, Fbxo2 inhibition increased cell motility and proliferation and inhibited cell apoptosis. WEE1 was identified as a novel substrate of Fbxo2 in RCC. Fbxo2 binds to the kinase domain of WEE1 through its FBA domain. Consistently, in xenograft mouse models, Fbxo2 knockdown increased tumor growth, whereas WEE1 depletion partially abolishes the tumorigenic effects caused by Fbxo2 silencing in vivo.

Conclusions: Our research revealed that Fbxo2 impedes the progression of RCC by interacting with WEE1, promoting its ubiquitination and degradation. Therefore, targeting the Fbxo2/WEE1 axis may represent a promising therapeutic strategy for treating RCC.