title: O-mannosylation and N-glycosylation: two coordinated mechanisms regulating the tumour suppressor functions of E-cadherin in cancer.
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.
authors.affiliation: Instituto de Investigação e Inovação em Saúde (I3S) / Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), 4200-465 Porto, Portugal.|Institute of Biomedical Sciences of Abel Salazar (ICBAS), University of Porto, 4050-313 Porto, Portugal.
authors.forename: Sandra
authors.initials: S
authors.lastname: Carvalho
authors.affiliation: Instituto de Investigação e Inovação em Saúde (I3S) / Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), 4200-465 Porto, Portugal.
authors.forename: Tiago
authors.initials: T
authors.lastname: Oliveira
authors.affiliation: Centre for Organismal Studies (COS) Heidelberg, Cell Chemistry, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Markus F
authors.initials: MF
authors.lastname: Bartels
authors.affiliation: Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, 565-0871 Osaka, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Miyoshi
authors.affiliation: Complex Carbohydrate Research Center, Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Pierce
authors.affiliation: Department of Biochemistry, Graduate School of Medicine, Osaka University, 565-0871 Osaka, Japan.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Taniguchi
authors.affiliation: Instituto de Investigação e Inovação em Saúde (I3S) / Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), 4200-465 Porto, Portugal.|Medical Faculty, University of Porto, 4200-319 Porto, Portugal.|Department of Pathology, Hospital S. Joao, 4200-319 Porto, Portugal.
authors.forename: Fátima
authors.initials: F
authors.lastname: Carneiro
authors.affiliation: Instituto de Investigação e Inovação em Saúde (I3S) / Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), 4200-465 Porto, Portugal.|Department of Pathology, Hospital S. Joao, 4200-319 Porto, Portugal.
authors.forename: Raquel
authors.initials: R
authors.lastname: Seruca
authors.affiliation: Instituto de Investigação e Inovação em Saúde (I3S) / Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), 4200-465 Porto, Portugal.|Institute of Biomedical Sciences of Abel Salazar (ICBAS), University of Porto, 4050-313 Porto, Portugal.|Department of Pathology, Hospital S. Joao, 4200-319 Porto, Portugal.
authors.forename: Celso A
authors.initials: CA
authors.lastname: Reis
authors.affiliation: Centre for Organismal Studies (COS) Heidelberg, Cell Chemistry, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Strahl
authors.affiliation: Instituto de Investigação e Inovação em Saúde (I3S) / Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), 4200-465 Porto, Portugal.|Medical Faculty, University of Porto, 4200-319 Porto, Portugal.
authors.forename: Salomé S
authors.initials: SS
authors.lastname: Pinho
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D015820:Cadherins / Q000378:metabolism*; D006031:Glycosylation; D006801:Humans; D008358:Mannose / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D011134:Polysaccharides; D011499:Protein Processing, Post-Translational / Q000502:physiology; D013274:Stomach Neoplasms / Q000378:metabolism* / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D015820:Cadherins; D011134:Polysaccharides; D025521:Tumor Suppressor Proteins; D008358:Mannose
keywords: E-cadherin; N-glycosylation; O-mannosylation; gastric cancer