Inverse to the impact of exogenous ARSB and pertinent to the development of melanoma, ARSB silencing increased CHST15 expression, abundance of C4,6S disaccharides, and activation of phospho(Tyr)-ROR1 and phospho(Ser473)-AKT1 and reduced nuclear FOXO3a and COP1 expression. Here, ARSB is linked to melanoma.