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

• Type: Article in International Scientific Journal
• Date: 2016

Authors

Carvalho, S (Author) Other; Catarino, TA (Author) Other; Dias, AM (Author) Other; Kato, M (Author) Other; Almeida, A (Author) Other; Hessling, B (Author) Other; Figueiredo, J (Author) Other; Gaertner, F (Author) Other; Sanches, JM (Author) Other; Ruppert, T (Author) Other; Miyoshi, E (Author) Other; Pierce, M (Author) Other; Carneiro F (Author) FMUP; Kolarich, D (Author) Other; Seruca, R (Author) Other; Yamaguchi, Y (Author) Other; Taniguchi, N (Author) Other; Celso Reis (Author) ICBAS; Pinho, SS (Author) Other

Journal

Title: Oncogene

Vol. 35

Pages: 1619-1631

ISSN: 0950-9232

Publisher: Springer Nature

Indexing

ISI Web of Knowledge - 71 Citations

Scopus - 75 Citations

Other information

Authenticus ID: P-00K-CCM

DOI: 10.1038/onc.2015.225

Abstract (EN): 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 beta 1,6 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.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 13