Involvement of abnormal dystroglycan expression and matriglycan levels in cancer pathogenesis

Dystroglycan (DG) is a glycoprotein composed of two subunits that remain non-covalently bound at the plasma membrane: α-DG, which is extracellular and heavily O -mannosyl glycosylated, and β-DG, an integral transmembrane polypeptide. α-DG is involved in the maintenance of tissue integrity and function in the adult, providing an O -glycosylation-dependent link for cells to their extracellular matrix. β-DG in turn contacts the cytoskeleton via dystrophin and participates in a variety of pathways transmitting extracellular signals to the nucleus. Increasing evidence exists of a pivotal role of DG in the modulation of normal cellular proliferation. In this context, deficiencies in DG glycosylation levels, in particular those affecting the so-called matriglycan structure, have been found in an ample variety of human tumors and cancer-derived cell lines. This occurs together with an underexpression of the DAG1 mRNA and/or its α-DG (core) polypeptide product or, more frequently, with a downregulation of β-DG protein levels. These changes are in general accompanied in tumor cells by a low expression of genes involved in the last steps of the α-DG O -mannosyl glycosylation pathway, namely POMT1 / 2 , POMGNT2 , CRPPA, B4GAT1 and LARGE1/2 . On the other hand, a series of other genes acting earlier in this pathway are overexpressed in tumor cells, namely DOLK , DPM1/2/3 , POMGNT1 , B3GALNT2 , POMK and FKTN , hence exerting instead a pro-oncogenic role. Finally, downregulation of β-DG, altered β-DG processing and/or impaired β-DG nuclear levels are increasingly found in human tumors and cell lines. It follows that DG itself, particular genes/proteins involved in its glycosylation and/or their interactors in the cell could be useful as biomarkers of certain types of human cancer, and/or as molecular targets of new therapies addressing these neoplasms.