Abstract

Cancer stem cells are pivotal in cancer progression, yet the mechanisms underlying the stemness properties of neuroblastoma cells remain largely unclear. By analyzing data from the TARGET‐NBL and GEO databases, WDR72 is identified as a cancer stem cell marker that significantly correlates with high‐risk of neuroblastoma and poor prognosis in neuroblastoma patients. It is found that knocking down WDR72 in neuroblastoma cells suppresses cell proliferation and migration, while inducing apoptosis. An increased expression of WDR72 is detected in neuroblastoma cells with enhanced stemness properties, while silencing WDR72 reduces the stemness of these cells. Mechanistically, we find that the upregulation of WDR72 is mediated by m6A modifications in its 3’ UTR induced by the METTL14‐IGF2BP1 axis. Further investigation into the downstream regulatory mechanisms of WDR72 demonstrates that WDR72 interacts with TRIM31, blocking the ubiquitination and subsequent degradation of the CBX8 protein. This interaction stabilizes CBX8, contributing to the maintenance of neuroblastoma cell stemness. This study reveals that the upregulation of WDR72 via the METTL14‐IGF2BP1 axis enhances the stemness properties of neuroblastoma cells by stabilizing CBX8 through interaction with TRIM31. These findings provide new insights into the molecular mechanisms driving neuroblastoma malignancy and offer potential therapeutic targets for patients with neuroblastoma. This study unveiled that METTL14 mediates m6A modification of WDR72 mRNA to stabilize and enhance WDR72 expression, which disrupts TRIM31‐mediated ubiquitination of CBX8 protein and retards its degradation, finally the elevated CBX8 contributes to tumor stemness.