Initiation of GalNAc-type O-glycosylation in the endoplasmic reticulum promotes cancer cell invasiveness

TY - JOUR

T1 - Initiation of GalNAc-type O-glycosylation in the endoplasmic reticulum promotes cancer cell invasiveness

AU - Gill, David J

AU - Tham, Keit Min

AU - Chia, Joanne

AU - Wang, Shyi Chyi

AU - Steentoft, Catharina

AU - Clausen, Henrik

AU - Bard-Chapeau, Emilie A

AU - Bard, Frederic A

PY - 2013/8/20

Y1 - 2013/8/20

N2 - 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.

AB - 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.

KW - Acetylgalactosamine

KW - Animals

KW - Antigens, Tumor-Associated, Carbohydrate

KW - Blotting, Western

KW - Cell Line

KW - Cell Movement

KW - Cloning, Molecular

KW - Endoplasmic Reticulum

KW - Fluorescent Antibody Technique

KW - Gene Expression Regulation, Neoplastic

KW - Glycosylation

KW - Glycosyltransferases

KW - Golgi Apparatus

KW - Humans

KW - Kaplan-Meier Estimate

KW - Mice

KW - Mice, Inbred BALB C

KW - Neoplasm Invasiveness

KW - Neoplasms

U2 - 10.1073/pnas.1305269110

DO - 10.1073/pnas.1305269110

M3 - Journal article

C2 - 23912186

SN - 0027-8424

VL - 110

SP - E3152-61

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 34

ER -