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Epigenetics: methylation-associated repression of heparan sulfate 3-O-sulfotransferase gene expression contributes to the invasive phenotype of H-EMC-SS chondrosarcoma cells

Catherine Bui^*, Mohamed Ouzzine^*, Ibtissam Talhaoui^*, Sheila Sharp, Kristian Prydz, Michael W. H. Coughtrie and Sylvie Fournel-Gigleux^*,1

^* UMR 7561 CNRS-University of Nancy I, Faculty of Medicine, Vandoeuvre-lès-Nancy, France;

Division of Medical Sciences, University of Dundee, Ninewells Hospital and Medical School, Dundee, UK; and

Department of Molecular Biosciences, University of Oslo, Oslo, Norway

¹ Correspondence: UMR CNRS 7561-University Henri Poincaré Nancy 1, Faculty of Medicine, BP 184, 54505 Vandœuvre-lès-Nancy, France. E-mail: sfg{at}medecine.uhp-nancy.fr

Heparan sulfate proteoglycans (HSPGs), strategically located at the cell-tissue-organ interface, regulate major biological processes, including cell proliferation, migration, and adhesion. These vital functions are compromised in tumors, due, in part, to alterations in heparan sulfate (HS) expression and structure. How these modifications occur is largely unknown. Here, we investigated whether epigenetic abnormalities involving aberrant DNA methylation affect HS biosynthetic enzymes in cancer cells. Analysis of the methylation status of glycosyltransferase and sulfotransferase genes in H-HEMC-SS chondrosarcoma cells showed a typical hypermethylation profile of 3-OST sulfotransferase genes. Exposure of chondrosarcoma cells to 5-aza-2'-deoxycytidine (5-Aza-dc), a DNA-methyltransferase inhibitor, up-regulated expression of 3-OST1, 3-OST2, and 3-OST3A mRNAs, indicating that aberrant methylation affects transcription of these genes. Furthermore, HS expression was restored on 5-Aza-dc treatment or reintroduction of 3-OST expression, as shown by indirect immunofluorescence microscopy and/or analysis of HS chains by anion-exchange and gel-filtration chromatography. Notably, 5-Aza-dc treatment of HEMC cells or expression of 3-OST3A cDNA reduced their proliferative and invading properties and augmented adhesion of chondrosarcoma cells. These results provide the first evidence for specific epigenetic regulation of 3-OST genes resulting in altered HSPG sulfation and point to a defect of HS-3-O-sulfation as a factor in cancer progression.—Bui, C., Ouzzine, M., Talhaoui, I., Sharp, S., Prydz, K., Coughtrie, M. W. H., Fournel-Gigleux, S. Epigenetics: methylation-associated repression of heparan sulfate 3-O-sulfotransferase gene expression contributes to the invasive phenotype of H-EMC-SS chondrosarcoma cells.

Key Words: tumor pathogenesis • proteoglycan synthesis • epigenetic regulation • glycosyltransferase