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Oncotarget. 2016 Oct 4;7(40):65231-65246. doi: 10.18632/oncotarget.11245.

O-mannosylation and N-glycosylation: two coordinated mechanisms regulating the tumour suppressor functions of E-cadherin in cancer.

Author information

1
Instituto de Investigação e Inovação em Saúde (I3S) / Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), 4200-465 Porto, Portugal.
2
Institute of Biomedical Sciences of Abel Salazar (ICBAS), University of Porto, 4050-313 Porto, Portugal.
3
Centre for Organismal Studies (COS) Heidelberg, Cell Chemistry, University of Heidelberg, 69120 Heidelberg, Germany.
4
Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, 565-0871 Osaka, Japan.
5
Complex Carbohydrate Research Center, Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602, USA.
6
Department of Biochemistry, Graduate School of Medicine, Osaka University, 565-0871 Osaka, Japan.
7
Medical Faculty, University of Porto, 4200-319 Porto, Portugal.
8
Department of Pathology, Hospital S. Joao, 4200-319 Porto, Portugal.

Abstract

Dysregulation of tumor suppressor protein E-cadherin is an early molecular event in cancer. O-mannosylation profile of E-cadherin is a newly-described post-translational modification crucial for its adhesive functions in homeostasis. However, the role of O-mannosyl glycans in E-cadherin-mediated cell adhesion in cancer and their interplay with N-glycans remains largely unknown. We herein demonstrated that human gastric carcinomas exhibiting a non-functional E-cadherin display a reduced expression of O-mannosyl glycans concomitantly with increased modification with branched complex N-glycans. Accordingly, overexpression of MGAT5-mediated branched N-glycans both in gastric cancer cells and transgenic mice models led to a significant decrease of O-mannosyl glycans attached to E-cadherin that was associated with impairment of its tumour suppressive functions. Importantly, overexpression of protein O-mannosyltransferase 2 (POMT2) induced a reduced expression of branched N-glycans which led to a protective effect of E-cadherin biological functions. Overall, our results reveal a newly identified mechanism of (dys)regulation of E-cadherin that occur through the interplay between O-mannosylation and N-glycosylation pathway.

KEYWORDS:

E-cadherin; N-glycosylation; O-mannosylation; gastric cancer

PMID:
27533452
PMCID:
PMC5323151
DOI:
10.18632/oncotarget.11245
[Indexed for MEDLINE]
Free PMC Article

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