Sec62 promotes stemness and chemoresistance of human colorectal cancer through activating Wnt/β-catenin pathway

Background: Cancer stem cell (CSC)-related chemoresistance leads to poor outcome of the patients with colorectal cancer (CRC). In this study, we identified the chemoresistance-relevant molecules and decipher the involved mechanisms to provide potential therapeutic target for CRC. We focused on Sec62, a novel target with significantly increased expression in chemoresistant CRC tissues, and further investigated its role in the progression of CRC. Methods: Through analyzing the differentially-expressed genes between chemoresistant and chemosensitive CRCs, we selected Sec62 as a novel chemoresistance-related target in CRC. The expression and clinical significance of Sec62 were determined by immunoblotting and immunohistochemistry in tissues and cell lines of CRC. The roles of Sec62 in drug resistance, stemness and tumorigenesis were evaluated in vitro and in vivo using functional experiments. GST pull-down, western blot, coimmunoprecipitation and Me-RIP assays were performed to further explore the downstream molecular mechanisms. Results: Sec62 upregulation was associated with the chemoresistance of CRC and poor outcome of CRC patients. Depletion of Sec62 sensitized CRC cells to chemotherapeutic drugs. Sec62 promoted the stemness of CRC cells through activating Wnt/beta-catenin signaling. Mechanistically, Sec62 bound to beta-catenin and inhibited the degradation of beta-catenin. Sec62 competitively disrupted the interaction between beta-catenin and APC to inhibit the beta-catenin destruction complex assembly. Moreover, Sec62 expression was upregulated by the m(6)A-mediated stabilization of Sec62 mRNA. Conclusions: Sec62 upregulated by the METTL3-mediated m(6)A modification promotes the stemness and chemoresistance of CRC by binding to beta-catenin and enhancing Wnt signalling. Thus, m(6)A modification-Sec62-beta-catenin molecular axis might act as therapeutic targets in improving treatment of CRC.