Ubiquitin-conjugating enzyme E2T confers chemoresistance of colorectal cancer by enhancing the signal propagation of Wnt/β-catenin pathway in an ERK-dependent manner

Abstract

Chemotherapy is a major therapeutic option for colorectal cancer; however, the frequently acquired chemoresistance greatly limits the treatment efficacy of chemotherapeutic agents. Ubiquitin-conjugating enzyme E2T (UBE2T) is emerging as a key player in the development of therapy resistance. However, whether UBE2T participates in the acquisition of chemoresistance in colorectal cancer remains undetermined. The present work aimed to specify the role of UBE2T in the development of chemoresistance in colorectal cancer and decipher any potential underlying mechanisms. Significant up-regulation of UBE2T was observed in the clinical specimens of chemoresistant colorectal cancer patients compared with chemosensitive patients. Compared with parental cells, the levels of UBE2T were also dramatically elevated in oxaliplatin (OXA)- and 5-fluorouracil (5-FU)-resistant colorectal cancer cells. Knockout of UBE2T rendered OXA- and 5-FU-resistant cells sensitive to OXA and 5-FU, respectively. Re-expression of UBE2T restored the chemoresistance of UBE2T-knockout OXA- and 5-FU-resistant cells. Mechanistically, phosphorylated GSK-3β, active β-catenin, c-myc and cyclin D1 levels were decreased in UBE2T-knockout OXA- and 5-FU-resistant cells, which were reversed by the re-expression of UBE2T. Moreover, knockout of UBE2T reduced the activation of ERK. The inhibition of ERK reversed the promotion effect of UBE2T on Wnt/β-catenin pathway. In vivo xenograft experiments demonstrated that knockout of UBE2T rendered the subcutaneous tumors formed by OXA-resistant cells sensitive to OXA. To conclude, UBE2T confers chemoresistance of colorectal cancer by boosting the signal propagation of the Wnt/β-catenin pathway in an ERK-dependent manner. Therefore, UBE2T could be a potential target for overcoming chemoresistance in the treatment of colorectal cancer.