Arylsulfatase B induces melanoma apoptosis by the ubiquitin ligase COP1.

Previous experiments in the syngeneic, murine, and subcutaneous model of malignant melanoma and human melanoma cells showed that treatment by recombinant human (rh) Arylsulfatase B (ARSB; N-acetylgalactosamine-4-sulfatase) markedly reduced the volume of tumors, improved survival, and inhibited invasiveness. In this report, the impact of ARSB on the progression of metastatic, pulmonary B16F10 melanomas in C57BL/6J mice is addressed, and the underlying apoptotic mechanism by which ARSB inhibits melanoma growth is identified. Exogenous ARSB, which has mannose 6-phosphate attachments, acts through insulin-like growth factor 2 receptor (IGF2R), a cation-independent mannose-6-phosphate receptor, and increases expression of constitutive photomorphogenic protein (COP)1. Expression of COP1, an E3 ubiquitin ligase, is increased by a decline in phospho(Ser473)-AKT1 and an increase in nuclear FOXO3a. ARSB-induced declines in carbohydrate sulfotransferase (CHST)15 expression and in transmembrane receptor tyrosine kinase-like orphan receptor 1 (ROR1) activation mediate the decline in phospho(Ser473)-AKT1. Inverse effects of rhARSB and ARSB knockdown on phospho(Ser473)-AKT1 indicate that ARSB acts as a tumor suppressor and that a decline in ARSB is pro-oncogenic. COP1, which inhibits ultraviolet-B stimulated growth in plants, suppresses nuclear ETS1 and ETS1-mediated expression of BCL2 in the murine melanomas and in human melanoma cells. These effects increase cytoplasmic cytochrome c, caspase-3/7 activation, and apoptosis. Since UVB exposure is recognized as a significant etiological factor in melanoma, identification of COP1 as an inhibitor of melanoma growth suggests the underlying presence of an ARSB-initiated growth inhibitory mechanism, analogous to that in plants, which contributes to the regulation of melanoma progression.