Preventing E-cadherin aberrant N-glycosylation at Asn-554 improves its critical function in gastric cancer

Authors and Affiliations:

Sandra Carvalho ^1,2, Telmo A. Catarino ¹, Ana M. Dias ^1,2, Masaki Kato ³, Andreia Almeida ^4,5, Bernd Hessling ⁶, Joana Figueiredo ¹, Fátima Gärtner ^1,2, João Miguel Sanches ⁷, Thomas Ruppert ⁶, Eiji Miyoshi ⁸, Michael Pierce ⁹, Fátima Carneiro ^1,10,11, Daniel Kolarich ⁴, Raquel Seruca ^1,10, Yoshiki Yamaguchi ³, Naoyuki Taniguchi ³, Celso A. Reis ^1,2,10, Salomé S. Pinho ^1,2

¹ Instituto de Investigação e Inovação em Saúde (Institute for Research and Innovation in Health), University of Porto, Portugal / Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto 4200-465, Portugal

² Institute of Biomedical Sciences of Abel Salazar (ICBAS), University of Porto, Porto 4050-313, Portugal

³ Systems Glycobiology Research Group, RIKEN-Max Planck Joint Research Center, RIKEN Global Research Cluster, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan

⁴ Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, 14424 Potsdam, Germany

⁵ Freie Universität Berlin, Institute of Chemistry and Biochemistry, Arnimallee 22, 14195 Berlin, Germany

⁶ Center for Molecular Biology, University of Heidelberg, 69120 Heidelberg, Germany

⁷ Institute for Systems and Robotics (ISR/IST), LARSyS, Instituto Superior Técnico,University of Lisbon, Lisboa, Portugal

⁸ Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, Osaka, Japan

⁹ Complex Carbohydrate Research Center, Department of Biochemistry and Molecular Biology, University of Georgia, 315 Riverbend Road, Athens, GA 30602, USA

¹⁰ Medical Faculty, University of Porto, Alameda Prof. Hernâni Monteiro 4200-319 Porto, Portugal

¹¹ Department of Pathology, Hospital S. Joao, Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal.

Abstract:

E-cadherin is a central molecule in the process of gastric carcinogenesis and its post-translational modifications by N-glycosylation have been described to induce a deleterious effect on cell adhesion associated with tumor cell invasion. However, the role that site-specific glycosylation of E-cadherin plays in its defective function in gastric cancer cells needs to be determined. Using transgenic mice models and human clinical samples we demonstrated that GnT-V-mediated glycosylation causes an abnormal pattern of E-cadherin expression in the gastric mucosa. In vitro models further indicated that among the four potential N-glycosylation sites of E-cadherin, Asn-554 is the key site that is selectively modified with β1,6 GlcNAc branched N-glycans catalyzed by GnT-V. This aberrant glycan modification on this specific asparagine site of E-cadherin was demonstrated to affect its critical functions in gastric cancer cells by affecting E-cadherin cellular localization, cis-dimer formation, molecular assembly and stability of the adherens junctions and cell-cell aggregation, which was further observed in human gastric carcinomas. Interestingly, manipulating this site-specific glycosylation, by preventing Asn-554 from receiving the deleterious branched structures, either by a mutation or by silencing GnT-V, resulted in a protective effect on E-cadherin, precluding its functional dysregulation and contributing to tumor suppression.

Journal: Oncogene

Link: http://www.nature.com/onc/journal/vaop/ncurrent/full/onc2015225a.html