WSB1 regulates c-Myc expression through ß-Catenin signalling and forms a feedforward circuit.

The dysregulation of transcription factors is widely associated with tumourigenesis. As the most well-defined transcription factor in multiple types of cancer, c-Myc can transform cells by transactivating various downstream genes. Given that there is no effective way to directly inhibit c-Myc, c-Myc targeting strategies hold great potential for cancer therapy. In this study, we found that WSB1, which has a highly positive correlation with c-Myc in 10 cancer cell lines and clinical samples, is a direct target gene of c-Myc, and can positively regulate c-Myc expression, which forms a feedforward circuit promoting cancer development. RNA sequencing results from Bel-7402 cells confirmed that WSB1 promoted c-Myc expression through the ß-Catenin pathway. Mechanistically, WSB1 affected ß-Catenin destruction complex-PPP2CA assembly and E3 ubiquitin ligase adaptor ß-TRCP recruitment, which inhibited the ubiquitination of ß-Catenin and transactivated c-Myc. Of interest, the effect of WSB1 on c-Myc was independent of its E3 ligase activity. Moreover, overexpressing WSB1 in the Bel-7402 xenograft model could further strengthen the tumour-driven effect of c-Myc overexpression. Thus, our findings revealed a novel mechanism involved in tumourigenesis in which the WSB1/c-Myc feedforward circuit played an essential role, highlighting a potential c-Myc intervention strategy in cancer treatment. Overall design: Bel-7402 cells stably overexpressing pCDH, pCDH-WSB1 and pCDH-?SOCS by lentivirus transfection were harvested and washed for 3 times with pre-cold PBS. Total RNA of the cells was extracted by TRIzol reagent and sent to Bohao Biotechnology (Shanghai, China) for RNA expression profiling.