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

• Autor(a) principal: Carvalho, S
• Data de Publicação: 2016
• Outros Autores: Catarino, TA, Dias, A, Kato, M, Almeida, A, Hessling, B, Figueiredo, J, Gärtner, F, Sanches, J, Ruppert, T, Miyoshi, E, Pierce, M, Carneiro, F, Kolarich, D, Seruca, R, Yamaguchi, Y, Taniguchi, N, Reis, CA, Pinho, SS
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: https://repositorio-aberto.up.pt/handle/10216/118212
• topic: Amino Acid Sequence; Animals; Asparagine/genetics; Cadherins/chemistry; Cadherins/genetics; Cadherins/metabolism; Cadherins/physiology; Catalytic Domain/genetics; Cell Line, Tumor; Dogs; Gastric Mucosa/metabolism; Gastric Mucosa/pathology; Glycosylation; HT29 Cells; Humans; Madin Darby Canine Kidney Cells; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular Sequence Data; Mutagenesis, Site-Directed; N-Acetylglucosaminyltransferases/antagonists & inhibitors; N-Acetylglucosaminyltransferases/genetics; N-Acetylglucosaminyltransferases/metabolism; Sequence Homology, Amino Acid; Stomach Neoplasms/genetics; Stomach Neoplasms/metabolism; Stomach Neoplasms/pathology

E-cadherin is a central molecule in the process of gastric carcinogenesis and its posttranslational 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 has in its defective function in gastric cancer cells needs to be determined. Using transgenic mice models and human clinical samples, we demonstrated that N-acetylglucosaminyltransferase V (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 ß1,6 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.