The c-MYC-WDR43 signalling axis promotes chemoresistance and tumour growth in colorectal cancer by inhibiting p53 activity

Oxaliplatin chemoresistance is a major challenge in the clinical treatment of colorectal cancer (CRC), which is one of the most common malignancies worldwide. In this study, we identified the tryptophan-aspartate repeat domain 43 (WDR43) as a potentially critical oncogenic factor in CRC pathogenesis through bioinformatics analysis. It was found that WDR43 is highly expressed in CRC tissues, and WDR43 overexpression is associated with poor prognosis of CRC patients. WDR43 knockdown significantly inhibits cell growth by arresting cell cycle and enhancing the effect of oxaliplatin chemotherapy both in vitro and in vivo. Mechanistically, upon oxaliplatin stimulation, c-MYC promotes the transcriptional regulation and expression of WDR43. WDR43 enhances the ubiquitination of p53 by MDM2 through binding to RPL11, thereby reducing the stability of the p53 protein, which induces proliferation and chemoresistance of CRC cells. Thus, the overexpression of WDR43 promotes CRC progression, and could be a potential therapeutic target of chemoresistance in CRC.

Automated summary

In this study, it was revealed that Oxaliplatin chemoresistance in colorectal cancer (CRC) is a major challenge in clinical treatment. The overexpression of WDR43 was found to be associated with poor prognosis in CRC patients. WDR43 knockdown inhibited cell growth and enhanced the effect of oxaliplatin chemotherapy by arresting cell cycle. Mechanistically, c-MYC promoted the transcriptional regulation and expression of WDR43. WDR43 enhanced the ubiquitination of p53 by MDM2 through binding to RPL11, leading to reduced stability of p53 protein and inducing proliferation and chemoresistance in CRC cells.