Glycoprotein glycosylation and cancer progression.
Glycosylation of glycoproteins and glycolipids is one of many molecular changes that accompany malignant transformation. GlcNAc-branched N-glycans and terminal Lewis antigen sequences have been observed to increase in some cancers, and to correlate with poor prognosis. Herein, we review evidence that beta1, 6GlcNAc-branching of N-glycans contributes directly to cancer progression, and we consider possible functions for the glycans. Mgat5 encodes N-acetylglucosaminyltransferase V (GlcNAc-TV), the Golgi enzyme required in the biosynthesis of beta1,6GlcNAc-branched N-glycans. Mgat5 expression is regulated by RAS-RAF-MAPK, a signaling pathway commonly activated in tumor cells. Ectopic expression of GlcNAc-TV in epithelial cells results in morphological transformation and tumor growth in mice, and over expression in carcinoma cells has been shown to induce metastatic spread. Ectopic expression of GlcNAc-TIII, an enzyme that competes with GlcNAc-TV for acceptor, suppresses metastasis in B16 melanoma cells. Furthermore, breast cancer progression and metastasis induced by a viral oncogene expressed in transgenic mice is markedly suppressed in a GlcNAc-TV-deficient background. Mgat5 gene expression and beta1, 6GlcNAc-branching of N-glycans are associated with cell motility, a required phenotype of malignant cells.
Dennis
J W
JW
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Ave., Rm. 876, M5G 1X5, Toronto, Ont., Canada. dennis@mshri.on.ca
Granovsky
M
M
Warren
C E
CE
D000606:Amino Sugars / Q000378:metabolism; D000818:Animals; D004847:Epithelial Cells / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006017:Glycolipids / Q000378:metabolism; D006023:Glycoproteins / Q000378:metabolism*; D006031:Glycosylation; D006801:Humans; D017351:N-Acetylglucosaminyltransferases / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D011134:Polysaccharides / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured
D000606:Amino Sugars; D006017:Glycolipids; D006023:Glycoproteins; D011134:Polysaccharides; D011948:Receptors, Antigen, T-Cell; C066929:polylactosamine; C000601122:Mgat5 protein, human; D017351:N-Acetylglucosaminyltransferases; C054599:beta-1,4-mannosyl-glycoprotein beta-1,4-N-acetylglucosaminyltransferase; C052254:alpha-1,6-mannosylglycoprotein beta 1,6-N-acetylglucosaminyltransferase