GALNT4-induced O-GalNAc glycosylation of MUC1 accelerates the invasive phenotype of PDAC.

Pancreatic ductal adenocarcinoma (PDAC), the predominant form of pancreatic cancer, remains a therapeutic challenge. While GALNT4 (a member of the N-acetylgalactosaminyltransferases family) shows significant upregulation in PDAC cells, its precise oncogenic mechanisms remain poorly understood. Bioinformatics analysis was performed to examine the expression of GALNT4 and MUC1 in pancreatic adenocarcinoma (PAAD) and to predict the glycosylation sites of MUC1. Functional assays were conducted to assess the effects of interfering with GALNT4/MUC1 on PDAC cell functions. Co-immunoprecipitation (Co-IP) and Vicia villosa agglutinin (VVA) pulldown assays were utilized to detect the interaction between GALNT4 and MUC1, as well as to evaluate the O-glycosylation levels of MUC1 and identify the glycosylation sites. In vivo validation was performed using PDAC animal models. High expression of GALNT4 in PDAC patients was associated with poor prognosis. Functional assays demonstrated that both GALNT4 and MUC1 promote the development of malignant phenotypes in PDAC cells, with in vivo experiments confirming GALNT4's tumor-promoting role. Mechanistically, GALNT4 induces O-GalNAc glycosylation at the S29 residue in the N-terminal domain of MUC1, thereby enhancing MUC1 protein stability. GALNT4-induced O-GalNAc glycosylation of MUC1 accelerates the formation of the invasive phenotype in PDAC, which could be a potential target for novel treatment.