Associação Portuguesa de Investigação em Cancro
O–mannosylation and N-glycosylation: two coordinated mechanisms regulating the tumour suppressor functions of E-cadherin in cancer
O–mannosylation and N-glycosylation: two coordinated mechanisms regulating the tumour suppressor functions of E-cadherin in cancer
Authors and Affiliations:
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
4Molecular Biochemistry and Clinical Investigation Department, Osaka University Graduate School of Medicine, 565-0871 Osaka, Japan
5Complex Carbohydrate Research Center, Department of Biochemistry and Molecular Biology of 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, Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal
*These authors have contributed equally to this work
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 ofMGAT5-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.
Journal: Oncotarget
