title: Initiation of GalNAc-type O-glycosylation in the endoplasmic reticulum promotes cancer cell invasiveness.
abstract: Invasiveness underlies cancer aggressiveness and is a hallmark of malignancy. Most malignant tumors have elevated levels of Tn, an O-GalNAc glycan. Mechanisms underlying Tn up-regulation and its effects remain unclear. Here we show that Golgi-to-endoplasmic reticulum relocation of polypeptide N-acetylgalactosamine-transferases (GalNAc-Ts) drives high Tn levels in cancer cell lines and in 70% of malignant breast tumors. This process stimulates cell adhesion to the extracellular matrix, as well as migration and invasiveness. The GalNAc-Ts lectin domain, mediating high-density glycosylation, is critical for these effects. Interfering with the lectin domain function inhibited carcinoma cell migration in vitro and metastatic potential in mice. We also show that stimulation of cell migration is dependent on Tn-bearing proteins present in lamellipodia of migrating cells. Our findings suggest that relocation of GalNAc-Ts to the endoplasmic reticulum frequently occurs upon cancerous transformation to enhance tumor cell migration and invasiveness through modification of cell surface proteins.
authors.affiliation: Institute of Molecular and Cell Biology, Proteos, Singapore 138673.
authors.forename: David J
authors.initials: DJ
authors.lastname: Gill
authors.forename: Keit Min
authors.initials: KM
authors.lastname: Tham
authors.forename: Joanne
authors.initials: J
authors.lastname: Chia
authors.forename: Shyi Chyi
authors.initials: SC
authors.lastname: Wang
authors.forename: Catharina
authors.initials: C
authors.lastname: Steentoft
authors.forename: Henrik
authors.initials: H
authors.lastname: Clausen
authors.forename: Emilie A
authors.initials: EA
authors.lastname: Bard-Chapeau
authors.forename: Frederic A
authors.initials: FA
authors.lastname: Bard
mesh_terms: D000116:Acetylgalactosamine / Q000378:metabolism*; D000818:Animals; D015295:Antigens, Tumor-Associated, Carbohydrate / Q000378:metabolism; D015153:Blotting, Western; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology; D003001:Cloning, Molecular; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006031:Glycosylation; D016695:Glycosyltransferases / Q000378:metabolism*; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D053208:Kaplan-Meier Estimate; D051379:Mice; D008807:Mice, Inbred BALB C; D009361:Neoplasm Invasiveness / Q000503:physiopathology*; D009369:Neoplasms / Q000378:metabolism / Q000503:physiopathology*
chemical_list: D015295:Antigens, Tumor-Associated, Carbohydrate; C040286:Tn antigen; C016467:Thomsen-Friedenreich antigen; D016695:Glycosyltransferases; D000116:Acetylgalactosamine
keywords: C1GalT; COPI; Src; Thomsen-Friedenreich antigen; invasion
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