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

// Sandra Carvalho 1, 2, * , Tiago Oliveira 1, * , Markus F. Bartels 3 , Eiji Miyoshi 4 , Michael Pierce 5 , Naoyuki Taniguchi 6 , Fatima Carneiro 1, 7, 8 , Raquel Seruca 1, 8 , Celso A. Reis 1, 2, 8 , Sabine Strahl 3 , Salome S. Pinho 1, 7 1 Instituto de Investigacao e Inovacao em Saude (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 * These authors have contributed equally to this work Correspondence to: Salome 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.