1. Loss of LARGE2 disrupts functional glycosylation of α-dystroglycan in prostate cancer
- Author
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Brian J. Smith, Michael R. Miller, Christopher S. Stipp, Daniel Beltrán-Valero de Bernabé, Melissa M. Meier, Kevin P. Campbell, Alison K. Esser, Qin Huang, Michael D. Henry, Charles F. Lynch, and Michael B. Cohen
- Subjects
musculoskeletal diseases ,Male ,congenital, hereditary, and neonatal diseases and abnormalities ,Glycosylation ,animal structures ,Cell Separation ,Biochemistry ,Epithelium ,Prostate cancer ,chemistry.chemical_compound ,Laminin ,Prostate ,Cell Movement ,Cell Line, Tumor ,medicine ,Dystroglycan ,Humans ,Neoplasm Invasiveness ,RNA, Small Interfering ,Dystroglycans ,Molecular Biology ,Cell Proliferation ,Gene knockdown ,biology ,Cell growth ,Cancer ,Glycosyltransferases ,Membrane Proteins ,Prostatic Neoplasms ,Molecular Bases of Disease ,Cell Biology ,medicine.disease ,musculoskeletal system ,Flow Cytometry ,Molecular biology ,Immunohistochemistry ,Extracellular Matrix ,Gene Expression Regulation, Neoplastic ,medicine.anatomical_structure ,chemistry ,Microscopy, Fluorescence ,biology.protein ,Cancer research ,Disease Progression ,tissues - 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. Background: Dystroglycan function is decreased in prostate and other cancers. Results: Decreased functional glycosylation of α-dystroglycan is clinically correlated with reduced LARGE2 and restoring its expression rescues dystroglycan function, reducing the invasive and proliferative potential of prostate cancer cells. Conclusion: LARGE2 regulates α-dystroglycan function in the prostatic epithelium. Significance: Loss of LARGE2 expression may contribute to prostate cancer progression.
- Published
- 2012