Uev1A Promotes Breast Cancer Cell Migration and EMT by Up-Regulating CT45A Expression via the AKT Pathway

Abstract IntroductionUEV1A encodes a ubiquitin-E2 variant closely associated with tumorigenesis and metastasis, but its underlying mechanism in promoting tumorigenesis remain to be investigated. MethodsIn this study, we experimentally manipulated UEV1A and CT45A gene expression and monitored their effects on cancer-related gene expression, cell migration and the signal transduction cascade.ResultsIt was found that UEV1A overexpression induces CT45A family gene expression in breast cancer cells. Indeed, ectopic expression of UEV1A is sufficient to induce CT45A and its downstream genes involved in tumorigenesis, epithelial-mesenchymal transition (EMT), stemness and metastasis, and promote cell migration and EMT. Consistently, depletion of CT45A abolishes the above effects, indicating that CT45A is a critical downstream effector of Uev1A. The Uev1A-induced cell migration and EMT is dependent on AKT signaling but independent of NF-κB signaling, indicating that CT45A acts downstream of the AKT pathway. ConclusionsBased on previous reports and observations in this study, we propose that the Ubc13-Uev1A complex activates AKT through K63-linked polyubiquitination, which leads to enhanced CT45A expression, stimulated cell migration and EMT. Since similar effects were also observed in a colorectal cancer cell line, we propose that the Ubc13/Uev1A-AKT-CT45A axis promotes tumorigenesis and metastasis in a broad range of tissues.