Oncotarget

Research Papers:

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

Sandra Carvalho, Tiago Oliveira, Markus F. Bartels, Eiji Miyoshi, Michael Pierce, Naoyuki Taniguchi, Fátima Carneiro, Raquel Seruca, Celso A. Reis, Sabine Strahl, Salomé S. Pinho _

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Oncotarget. 2016; 7:65231-65246. https://doi.org/10.18632/oncotarget.11245

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Abstract

Sandra Carvalho1,2,*, Tiago Oliveira1,*, Markus F. Bartels3, Eiji Miyoshi4, Michael Pierce5, Naoyuki Taniguchi6, Fátima Carneiro1,7,8, Raquel Seruca1,8, Celso A. Reis1,2,8, Sabine Strahl3, Salomé S. Pinho1,7

1Instituto de Investigação e Inovação em Saúde (I3S) / Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), 4200-465 Porto, Portugal

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

3Centre for Organismal Studies (COS) Heidelberg, Cell Chemistry, University of Heidelberg, 69120 Heidelberg, Germany

4Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, 565-0871 Osaka, Japan

5Complex Carbohydrate Research Center, Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602, USA

6Department of Biochemistry, Graduate School of Medicine, Osaka University, 565-0871 Osaka, Japan

7Medical Faculty, University of Porto, 4200-319 Porto, Portugal

8Department of Pathology, Hospital S. Joao, 4200-319 Porto, Portugal

*These authors have contributed equally to this work

Correspondence to:

Salomé S. Pinho, email: salomep@ipatimup.pt

Keywords: E-cadherin, O-mannosylation, N-glycosylation, gastric cancer

Received: May 09, 2016    Accepted: August 01, 2016    Published: August 12, 2016

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.


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