Abstract
Notch signaling receptors, ligands, and their downstream target genes are dysregulated in pancreatic ductal adenocarcinoma (PDAC), suggesting a role of Notch signaling in pancreatic tumor development and progression. However, dysregulation of Notch signaling by post-translational modification of Notch receptors remains poorly understood. Here, we analyzed the Notch-modifying glycosyltransferase involved in the regulation of the ligand-dependent Notch signaling pathway. Bioinformatic analysis revealed that the expression of epidermal growth factor (EGF) domain-specific O-linked N-acetylglucosamine (EOGT) and Lunatic fringe (LFNG) positively correlates with a subset of Notch signaling genes in PDAC. The lack of EOGT or LFNG expression inhibited the proliferation and migration of Panc-1 cells, as observed by the inhibition of Notch activation. EOGT expression is significantly increased in the basal subtype, and low expression of both EOGT and LFNG predicts better overall survival in PDAC patients. These results imply potential roles for EOGT- and LFNG-dependent Notch signaling in PDAC.
Highlights
Pancreatic cancer is one of the most fatal malignancies, which causes cancer mortality in most developed countries
Our study indicated critical roles for EOGT- and Lunatic fringe (LFNG)-dependent Notch signaling in pancreatic ductal adenocarcinoma (PDAC)
Contribution of EOGT and LFNG to Notch Signaling in PDAC
Summary
Pancreatic cancer is one of the most fatal malignancies, which causes cancer mortality in most developed countries. Notch signaling is considered a molecular target for different malignancies [8,9]. In mouse models, both activation and inhibition of Notch signaling promote PDAC development and progression [10,11,12,13]. EOGT is highly expressed in endothelial cells and regulates optimal vascular integrity and development by enhancing DLL ligand-mediated Notch signaling [24,26]. There is no evidence showing that EOGT-mediated O-GlcNAcylation participates in the development and progression of cancer, including PDAC. In addition to EOGT, Fringe genes are involved in the regulation of ligand-dependent Notch signaling pathway. We showed—for the first time—that EOGT impacts cell proliferation and migration in cancer cells
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