title: Modulation of N-glycosylation by mesalamine facilitates membranous E-cadherin expression in colon epithelial cells.
abstract: Genome wide association studies have implicated intestinal barrier function genes in the pathogenesis of ulcerative colitis. One of such loci CDH1, encoding E-cadherin, a transmembrane glycoprotein with known tumor suppressor functions, is also linked to the susceptibility to colorectal cancer. Loss of membranous E-cadherin expression is common in both colitis and cancer. We have recently demonstrated that mesalamine (5-ASA); the anti-inflammatory drug used to treat ulcerative colitis, induces membranous expression of E-cadherin and increases intercellular adhesion. Using colorectal cancer epithelial cells with aberrant E-cadherin expression, we investigated the mechanism underlying such an effect of 5-ASA. Post-translational modification of E-cadherin glycosylation was analyzed by biotin/streptavidin detection of sialylated glycoproteins. GnT-III (N-acetylglucosaminyltransferase III) expression was assessed by qRT-PCR, Western blot and immunofluorescence. GnT-III activity was analyzed by reactivity with E-4/L-4-PHA. Expression, localization and interaction of E-cadherin and β-catenin were analyzed by Western blot, immunocytochemistry and RNA interference. 5-ASA activity modulated E-cadherin glycosylation and increased both mRNA and protein levels of GnT-III and its activity as detected by increased E4-lectin reactivity. Intestinal APC(Min) polyps in mice showed low expression of GnT-III and 5-ASA was effective in increasing its expression. The data demonstrated that remodeling of glycans by GnT-III mediated bisect glycosylation, contributes to the membranous retention of E-cadherin by 5-ASA; facilitating intercellular adhesion. Induction of membranous expression of E-cadherin by 5-ASA is a novel mechanism for mucosal healing in colitis that might impede tumor progression by modulation of GnT-III expression.
authors.affiliation: Medical University of Vienna, Department of Internal Medicine III, Division of Gastroenterology and Hepatology and Christian Doppler Laboratory for Molecular Cancer Chemoprevention, Währinger Gürtel, 18-20A-1090 Vienna, Austria.
authors.forename: Vineeta
authors.initials: V
authors.lastname: Khare
authors.affiliation: Medical University of Vienna, Department of Internal Medicine III, Division of Gastroenterology and Hepatology and Christian Doppler Laboratory for Molecular Cancer Chemoprevention, Währinger Gürtel, 18-20A-1090 Vienna, Austria.
authors.forename: Michaela
authors.initials: M
authors.lastname: Lang
authors.affiliation: Medical University of Vienna, Department of Internal Medicine III, Division of Gastroenterology and Hepatology and Christian Doppler Laboratory for Molecular Cancer Chemoprevention, Währinger Gürtel, 18-20A-1090 Vienna, Austria.
authors.forename: Kyle
authors.initials: K
authors.lastname: Dammann
authors.affiliation: Medical University of Vienna, Department of Internal Medicine III, Division of Gastroenterology and Hepatology and Christian Doppler Laboratory for Molecular Cancer Chemoprevention, Währinger Gürtel, 18-20A-1090 Vienna, Austria.
authors.forename: Christoph
authors.initials: C
authors.lastname: Campregher
authors.affiliation: Medical University of Vienna, Department of Internal Medicine III, Division of Gastroenterology and Hepatology and Christian Doppler Laboratory for Molecular Cancer Chemoprevention, Währinger Gürtel, 18-20A-1090 Vienna, Austria.
authors.forename: Alex
authors.initials: A
authors.lastname: Lyakhovich
authors.affiliation: Medical University of Vienna, Department of Internal Medicine III, Division of Gastroenterology and Hepatology and Christian Doppler Laboratory for Molecular Cancer Chemoprevention, Währinger Gürtel, 18-20A-1090 Vienna, Austria. Electronic address: christoph.gasche@meduniwien.ac.at.
authors.forename: Christoph
authors.initials: C
authors.lastname: Gasche
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D015820:Cadherins / Q000096:biosynthesis*; D003106:Colon / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006031:Glycosylation / Q000187:drug effects; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D019804:Mesalamine / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D015820:Cadherins; D019804:Mesalamine
keywords: 5-ASA; AJ; CRC; E-cadherin; Glycosylation; GnT-III; IBD; N-acetylglucosaminyltransferase-III; PAK1; UC; Ulcerative colitis; adherens junction; colorectal cancer; inflammatory bowel diseases; p21 activated kinase 1; ulcerative colitis