Tumor suppressor function of laminin-binding alpha-dystroglycan requires a distinct beta3-N-acetylglucosaminyltransferase

Proc Natl Acad Sci U S A. 2009 Jul 21;106(29):12109-14. doi: 10.1073/pnas.0904515106. Epub 2009 Jul 8.

Abstract

Alpha-dystroglycan (alpha-DG) represents a highly glycosylated cell surface molecule that is expressed in the epithelial cell-basement membrane (BM) interface and plays an essential role in epithelium development and tissue organization. The alpha-DG-mediated epithelial cell-BM interaction is often impaired in invasive carcinomas, yet roles and underlying mechanisms of such an impaired interaction in tumor progression remain unclear. We report here a suppressor function of laminin-binding glycans on alpha-DG in tumor progression. In aggressive prostate and breast carcinoma cell lines, laminin-binding glycans are dramatically decreased, although the amount of alpha-DG and beta-dystroglycan is maintained. The decrease of laminin-binding glycans and consequent increased cell migration were associated with the decreased expression of beta3-N-acetylglucosaminyltransferase-1 (beta3GnT1). Forced expression of beta3GnT1 in aggressive cancer cells restored the laminin-binding glycans and decreased tumor formation. beta3GnT1 was found to be required for laminin-binding glycan synthesis through formation of a complex with LARGE, thus regulating the function of LARGE. Interaction of the laminin-binding glycans with laminin and other adhesive molecules in BM attenuates tumor cell migratory potential by antagonizing ERK/AKT phosphorylation induced by the components in the ECM. These results identify a previously undescribed role of carbohydrate-dependent cell-BM interaction in tumor suppression and its control by beta3GnT1 and LARGE.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms / enzymology
  • Breast Neoplasms / pathology
  • Cell Movement
  • Dystroglycans / metabolism*
  • Extracellular Matrix / metabolism
  • Female
  • Glycosylation
  • Humans
  • Integrins / metabolism
  • Laminin / metabolism*
  • Ligands
  • Male
  • Models, Biological
  • N-Acetylglucosaminyltransferases / metabolism*
  • Phenotype
  • Polysaccharides / metabolism
  • Prostatic Neoplasms / enzymology
  • Prostatic Neoplasms / pathology
  • Protein Binding
  • Signal Transduction
  • Tumor Suppressor Proteins / metabolism*

Substances

  • Integrins
  • Laminin
  • Ligands
  • Polysaccharides
  • Tumor Suppressor Proteins
  • Dystroglycans
  • LARGE1 protein, human
  • N-Acetylglucosaminyltransferases