SAD1/UNC84 domain protein-2 (SUN2) plays a tumor suppressor role in various types of cancer by inhibiting cancer cell proliferation, migration and promoting apoptosis. However, the post-translational regulation of SUN2 and the cellular mechanism responsible for its proteasomal degradation remains largely unknown. Here, we show that FBXO2, an E3 ubiquitin ligase of the F-box proteins (FBPs) family targets glycosylated SUN2 for ubiquitination and degradation via the ubiquitin-proteasome system (UPS). By integrating the Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and the Encyclopedia of Cancer Cell Lines (CCLE) databases, we revealed that FBXO2 was selectively highly expressed in ovarian cancer (OV) tissues and cells. Patients with relatively high FBXO2 expression levels were associated with worse prognosis. Manipulation of the expression of FBXO2 affecting ovarian cancer cell proliferation, migration/invasion in vitro, and tumor growth in mice in vivo. The transcription factor SOX6 promoted FBXO2 expression by recognizing a putative response element localized on the promoter region of FBXO2. Abnormally highly expressed FBXO2 recognized and targeted glycosylated SUN2 protein for ubiquitination-depended degradation to prevent cell apoptosis, promote cell proliferation, and ultimately promote the progression of OV. Thus, we revealed a new SOX6-FBXO2-SUN2 axis that contributed to the development of OV, and targeting this axis may represent an effective OV treatment strategy.

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SEMA6A is a multifunctional transmembrane semaphorin protein that participates in various cellular processes, including axon guidance, cell migration, and cancer progression. However, the role of SEMA6A in clear cell renal cell carcinoma (ccRCC) is unclear. Based on high-throughput sequencing data, here we report that SEMA6A is a novel target gene of the VHL-HIF-2α axis and overexpressed in ccRCC. Chromatin immunoprecipitation and reporter assays revealed that HIF-2α directly activated SEMA6A transcription in hypoxic ccRCC cells. Wnt/β-catenin pathway activation is correlated with the expression of SEMA6A in ccRCC; the latter physically interacted with SEC62 and promoted ccRCC progression through SEC62-dependent β-catenin stabilization and activation. Depletion of SEMA6A impaired HIF-2α-induced Wnt/β-catenin pathway activation and led to defective ccRCC cell proliferation both in vitro and in vivo. SEMA6A overexpression promoted the malignant phenotypes of ccRCC, which was reversed by SEC62 depletion. Collectively, this study revealed a potential role for VHL-HIF-2α-SEMA6A-SEC62 axis in the activation of Wnt/β-catenin pathway. Thus, SEMA6A may act as a potential therapeutic target, especially in VHL-deficient ccRCC.

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