E-cadherin and adherens-junctions stability in gastric carcinoma: Functional implications of glycosyltransferases involving N-glycan branching biosynthesis, N-acetylglucosaminyltransferases III and V

• Published in: Biochimica et biophysica acta Vol. 1830; no. 3; pp. 2690 - 2700
• Main Authors: Pinho, Salomé S., Figueiredo, Joana, Cabral, Joana, Carvalho, Sandra, Dourado, Joana, Magalhães, Ana, Gärtner, Fátima, Mendonça, Ana Maria, Isaji, Tomoya, Gu, Jianguo, Carneiro, Fátima, Seruca, Raquel, Taniguchi, Naoyuki, Reis, Celso A.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.03.2013
• Subjects: Adherens Junctions - genetics; Adherens Junctions - metabolism; Adherens-junctions; biosynthesis; cadherins; Cadherins - genetics; Cadherins - metabolism; carcinoma; Carcinoma - genetics; Carcinoma - metabolism; Carcinoma - pathology; Cell Adhesion; Cell Line, Tumor; cell membranes; Cell Movement; DNA; E-cadherin; Endocytosis; Gastric cancer; Gene Expression Regulation, Neoplastic; Glycosaminoglycans - metabolism; Glycosyltransferases; Humans; Kinetics; mutation; N-Acetylglucosaminyltransferases - genetics; N-Acetylglucosaminyltransferases - metabolism; N-glycosylation; Neoplasm Invasiveness; RNA; Signal Transduction; stomach neoplasms; Stomach Neoplasms - genetics; Stomach Neoplasms - metabolism; Stomach Neoplasms - pathology; Adherens-junctions; Gastric cancer; E-cadherin; N-glycosylation; Glycosyltransferases
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/j.bbagen.2012.10.021

E-cadherin is a cell–cell adhesion molecule and the dysfunction of which is a common feature of more than 70% of all invasive carcinomas, including gastric cancer. Mechanisms behind the loss of E-cadherin function in gastric carcinomas include mutations and silencing at either the DNA or RNA level. Nevertheless, in a high percentage of gastric carcinoma cases displaying E-cadherin dysfunction, the mechanism responsible for E-cadherin dysregulation is unknown. We have previously demonstrated the existence of a bi-directional cross-talk between E-cadherin and two major N-glycan processing enzymes, N-acetylglucosaminyltransferase-III or -V (GnT-III or GnT-V). In the present study, we have characterized the functional implications of the N-glycans catalyzed by GnT-III and GnT-V on the regulation of E-cadherin biological functions and in the molecular assembly and stability of adherens-junctions in a gastric cancer model. The results were validated in human gastric carcinoma samples. We demonstrated that GnT-III induced a stabilizing effect on E-cadherin at the cell membrane by inducing a delay in the turnover rate of the protein, contributing for the formation of stable and functional adherens-junctions, and further preventing clathrin-dependent E-cadherin endocytosis. Conversely, GnT-V promotes the destabilization of E-cadherin, leading to its mislocalization and unstable adherens-junctions with impairment of cell–cell adhesion. This supports the role of GnT-III on E-cadherin-mediated tumor suppression, and GnT-V on E-cadherin-mediated tumor invasion. These results contribute to fill the gap of knowledge of those human carcinoma cases harboring E-cadherin dysfunction, opening new insights into the molecular mechanisms underlying E-cadherin regulation in gastric cancer with potential translational clinical applications. ► E-cadherin is often dysregulated in invasive gastric carcinomas. ► We characterized the functional role of N-glycans on E-cadherin in gastric cancer. ► GnT-III-mediated glycosylation has a stabilizer effect on E-cadherin functions. ► GnT-V-mediated glycosylation has a destabilizer effect on E-cadherin functions. ► Gastric carcinoma cases exhibit E-cadherin modifications with deleterious N-glycans.