WDR3 drives pancreatic cancer metastasis by enhancing TGF-α mRNA stability through YTHDC1.

Pancreatic cancer is a highly aggressive malignancy associated with poor prognosis and early metastasis. However, the molecular mechanisms underlying its invasive behavior remain incompletely understood. Here, we identified WD repeat domain 3 (WDR3) as a key driver of pancreatic cancer cell invasion. WDR3 expression is significantly elevated in liver metastatic lesions and is correlated with disease progression. Functional assays revealed that WDR3 promotes cell migration and invasion by upregulating transforming growth factor-α (TGF-α). Mechanistically, WDR3 interacts with the m6A reader YTH domain-containing protein 1 (YTHDC1) and facilitates its K63-linked ubiquitination, resulting in increased cytoplasmic localization of YTHDC1. This modification enhances the stability of TGF-α mRNA, thereby promoting its expression. Knockdown of either WDR3 or YTHDC1 impairs TGF-α expression and suppresses cancer cell invasiveness, whereas YTHDC1 overexpression restores the metastatic phenotype in WDR3-deficient cells. Our findings reveal a novel WDR3-YTHDC1-TGF-α axis that drives pancreatic cancer progression and suggest that targeting WDR3 may be a promising therapeutic strategy.