Restoring O-glycosylation and expression of MUC2 limits progression of colorectal cancer

Abstract Colorectal cancer (CRC) progression is associated with intestinal barrier dysfunction, yet the molecular mechanisms governing mucin glycosylation remain unclear. This study aims to investigate the regulatory pathway controlling MUC2 expression and O-glycosylation in CRC and assess the therapeutic potential of rosiglitazone in restoring mucosal integrity. In this study, B3GNT6 was identified as a key glycosyltransferase that promotes MUC2 O-glycosylation and protein stability. KLF4 was shown to transcriptionally regulate both B3GNT6 and MUC2, with its activity modulated by PPARg. Treatment with the PPARg agonist rosiglitazone activated the PPARg-KLF4-B3GNT6 axis, restoring MUC2 function and enhancing the mucus barrier integrity. These findings highlight a novel therapeutic avenue for CRC by targeting mucin glycosylation.