UBE2T promotes beta-catenin nuclear translocation in hepatocellular carcinoma through MAPK/ERK-dependent activation

Ubiquitin-conjugating enzyme E2T (UBE2T) has been implicated in many types of cancer including hepatocellular carcinoma (HCC). Epithelial-mesenchymal transition (EMT) process plays a fundamental role during tumor metastasis and progression. However, the molecular mechanisms underlying EMT in HCC in accordance with UBE2T still remain unknown. In this study, we showed that UBE2T overexpression augmented the oncogenic properties and specifically EMT in HCC cell lines, while its silencing attenuated them. UBE2T affected the activation of EMT-associated signaling pathways: MAPK/ERK, AKT/mTOR, and Wnt/beta-catenin. In addition, we revealed that the epithelial protein complex of E-cadherin/beta-catenin, a vital regulator of signal transduction in tumor initiation and progression, was totally disrupted at the cell membrane. In particular, we observed that UBE2T overexpression led to E-cadherin loss accompanied by a simultaneous elevation of both cytoplasmic and nuclear beta-catenin, while its silencing resulted in a strong E-cadherin turnover at the cell membrane. Interestingly, chemical inhibition of the MAPK/ERK, AKT/mTOR, and Wnt/beta-catenin signaling pathways demonstrated that the nuclear translocation of beta-catenin and subsequent EMT was enhanced mainly by MAPK/ERK. Collectively, our findings demonstrate the UBE2T/MAPK-ERK/beta-catenin axis as a critical regulator of cell state transition and EMT in HCC.