Oncogenes and Tumor Suppressors Enhanced Tumorigenic Potential of Colorectal Cancer Cells by

Heparan sulfate endosulfatase-1 and-2 (SULF1 and SULF2) are two important extracellular 6-O-endosulfatases that remove 6-O sulfate groups of N-glucosamine along heparan sulfate (HS) proteoglycan chains often found in the extracellular matrix. The HS sulfation pattern influences signaling events at the cell surface, which are critical for interactions with growth factors and their receptors. SULFs are overexpressed in several types of human tumors, but their role in cancer is still unclear because their molecular mechanism has not been fully explored and under-stood. To further investigate the functions of these sulfatases in tumorigenesis, stable overexpression models of these genes were generated in the colorectal cancer cells, Caco-2 and HCT-116. Importantly, mimicking overexpression of these sulfatases resulted in increased viability and proliferation, and augmented cell migration. These effects were reverted by shRNA-mediated knockdown of SULF1 or SULF2 and by the addition of unfrac-tionated heparin. Detailed structural analysis of HS from cells overexpressing SULFs showed reduction in the trisulfated dis-accharide UA(2S)-GlcNS(6S) and corresponding increase in UA(2S)-GlcNS disaccharide, as well as an unexpected rise in less common disaccharides containing GlcNAc(6S) residues. More-over, cancer cells transfected with SULFs demonstrated increased Wnt signaling. In summary, SULF1 or SULF2 overexpression contributes to colorectal cancer cell proliferation, migration, and invasion. Implications: This study reveals that sulfatases have oncogenic effects in colon cancer cells, suggesting an important role for these enzymes in cancer progression. Mol Cancer Res; 13(3); 510– 23. 2014 AACR