Loss of alpha-dystroglycan laminin binding in epithelium-derived cancers is caused by silencing of LARGE.
The interaction between epithelial cells and the extracellular matrix is crucial for tissue architecture and function and is compromised during cancer progression. Dystroglycan is a membrane receptor that mediates interactions between cells and basement membranes in various epithelia. In many epithelium-derived cancers, beta-dystroglycan is expressed, but alpha-dystroglycan is not detected. Here we report that alpha-dystroglycan is correctly expressed and trafficked to the cell membrane but lacks laminin binding as a result of the silencing of the like-acetylglucosaminyltransferase (LARGE) gene in a cohort of highly metastatic epithelial cell lines derived from breast, cervical, and lung cancers. Exogenous expression of LARGE in these cancer cells restores the normal glycosylation and laminin binding of alpha-dystroglycan, leading to enhanced cell adhesion and reduced cell migration in vitro. Our findings demonstrate that LARGE repression is responsible for the defects in dystroglycan-mediated cell adhesion that are observed in epithelium-derived cancer cells and point to a defect of dystroglycan glycosylation as a factor in cancer progression.
de Bernabé
Daniel Beltrán-Valero
DB
Howard Hughes Medical Institute, University of Iowa, Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa 52242-1101, USA.
Inamori
Kei-Ichiro
K
Yoshida-Moriguchi
Takako
T
Weydert
Christine J
CJ
Harper
Hollie A
HA
Willer
Tobias
T
Henry
Michael D
MD
Campbell
Kevin P
KP
D002448:Cell Adhesion; D045744:Cell Line, Tumor; D049030:Dystroglycans / Q000378:metabolism*; D004848:Epithelium / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006031:Glycosylation; D006367:HeLa Cells; D006801:Humans; D007797:Laminin / Q000378:metabolism*; D008954:Models, Biological; D017351:N-Acetylglucosaminyltransferases / Q000378:metabolism*; D009362:Neoplasm Metastasis; D011485:Protein Binding; D012878:Skin Neoplasms / Q000378:metabolism*
D007797:Laminin; D049030:Dystroglycans; C117674:LARGE1 protein, human; D017351:N-Acetylglucosaminyltransferases