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Although the vast majority of melanomas are characterized by a high metastatic potential, if detected early, melanoma can have a good prognostic outcome. However, once metastasised, the prognosis is bleak. We showed previously that uronyl-2-O sulfotransferase (Ust) and 2-O sulfation of chondroitin/dermatan sulfate (CS/DS) are involved in cell migration. To demonstrate an impact of 2-O sulfation in metastasis we knocked-down  Ust  in mouse melanoma cells. This significantly reduced the amount of Ust protein and enzyme activity. Furthermore,  in vitro  cell motility and adhesion were significantly reduced correlating with the decrease of cellular Ust protein. Single cell migration of B16V shUst(16)  cells showed a decreased cell movement phenotype. The adhesion of B16V cells to fibronectin depended on α5β1 but not αvβ3 integrin. Inhibition of glycosaminoglycan sulfation or blocking fibroblast growth factor receptor (FgfR) reduced α5 integrin in B16V cell lines. Interestingly, FgfR1 expression and activation was reduced in  Ust  knock-down cells.  In vivo , pulmonary metastasis of B16V shUst  cells was prevented due to a reduction of α5 integrin. As a proof of concept  UST  knock-down in human melanoma cells also showed a reduction in  ITGa 5 and adhesion. This is the first study showing that Ust, and consequently 2-O sulfation of the low affinity receptor for FgfR CS/DS, reduces  Itga 5 and leads to an impaired adhesion and migration of melanoma cells.

Melanoma Cell Adhesion and Migration Is Modulated by the Uronyl 2-O Sulfotransferase