title: Loss of LARGE2 disrupts functional glycosylation of α-dystroglycan in prostate cancer.
abstract: Dystroglycan (DG) is a cell surface receptor for extracellular matrix proteins and is involved in cell polarity, matrix organization, and mechanical stability of tissues. Previous studies documented loss of DG protein expression and glycosylation in a variety of cancer types, but the underlying mechanisms and the functional consequences with respect to cancer progression remain unclear. Here, we show that the level of expression of the βDG subunit as well as the glycosylation status of the αDG subunit inversely correlate with the Gleason scores of prostate cancers; furthermore, we show that the functional glycosylation of αDG is substantially reduced in prostate cancer metastases. Additionally, we demonstrate that LARGE2 (GYLTL1B), a gene not previously implicated in cancer, regulates functional αDG glycosylation in prostate cancer cell lines; knockdown of LARGE2 resulted in hypoglycosylation of αDG and loss of its ability to bind laminin-111 while overexpression restored ligand binding and diminished growth and migration of an aggressive prostate cancer cell line. Finally, our analysis of LARGE2 expression in human cancer specimens reveals that LARGE2 is significantly down-regulated in the context of prostate cancer, and that its reduction correlates with disease progression. Our results describe a novel molecular mechanism to account for the commonly observed hypoglycosylation of αDG in prostate cancer.
authors.affiliation: Department of Molecular Physiology and Biophysics, The Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA.
authors.forename: Alison K
authors.initials: AK
authors.lastname: Esser
authors.forename: Michael R
authors.initials: MR
authors.lastname: Miller
authors.forename: Qin
authors.initials: Q
authors.lastname: Huang
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Meier
authors.forename: Daniel
authors.initials: D
authors.lastname: Beltran-Valero de Bernabé
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Stipp
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Campbell
authors.forename: Charles F
authors.initials: CF
authors.lastname: Lynch
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Smith
authors.forename: Michael B
authors.initials: MB
authors.lastname: Cohen
authors.forename: Michael D
authors.initials: MD
authors.lastname: Henry
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002469:Cell Separation; D018450:Disease Progression; D049030:Dystroglycans / Q000235:genetics* / Q000502:physiology*; D004848:Epithelium / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006031:Glycosylation; D016695:Glycosyltransferases / Q000235:genetics* / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D007797:Laminin / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000502:physiology*; D008856:Microscopy, Fluorescence / Q000379:methods; D009361:Neoplasm Invasiveness; D011471:Prostatic Neoplasms / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism
chemical_list: D007797:Laminin; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D049030:Dystroglycans; D016695:Glycosyltransferases; C500430:LARGE2 protein, human