Abstract C005: Arylsulfatase B inhibits progression of malignant melanoma by COP1-mediated apoptosis in syngeneic and humanized mouse models

Abstract The enzyme Arylsulfatase B (ARSB; N-acetylgalactosamine-4-sulfatase) removes the 4-sulfate group at the non-reducing end of chondroitin 4-sulfate (C4S) and is required for C4S degradation in mammalian cells. Congenital, inactivating mutations of ARSB are the cause of Mucopolysaccharidosis (MPS) VI, and replacement therapy with rhARSB is routinely used with benefit for MPS VI patients. In several malignancies, including malignant melanoma, prostate, mammary, and colon, ARSB expression and activity are reduced, leading to increased C4S. Recently, we have reported that treatment of syngeneic B16F10 melanomas by recombinant human ARSB reduces the volume of subcutaneous and metastatic pulmonary melanomas and improves survival (PMID:37813168; PMID:40562100). Similar effects of rhARSB are evident following treatment of A375 melanomas in the humanized PBMC NSG mouse model. ARSB enhances apoptosis in melanomas by increasing expression of the E3 ubiquitin ligase constitutive photomorphogenic (COP)1, a known inhibitor of responses to ultraviolet B. In melanomas, COP1 reduces ETS1 and expression of BCL2, leading to increase in cleaved caspase-3. The increase in COP1 follows rhARSB-induced declines in Ras GTPase activity and phospho(Ser473)-AKT1, leading to increase in nuclear FOXO3 and COP1 promoter activation. The cellular signaling and transcriptional effects of rhARSB are mediated by changes in chondroitin 4-sulfation, which affect C4S binding with critical molecules, including galectin-3, SHP2 (PTPN11), and IL-8. Galectin-3 binds less when ARSB is reduced, leading to increased availability to act as a co-transcriptional activator with Sp1 or AP1. In contrast, SHP2, the ubiquitous non-receptor tyrosine phosphatase, binds more with C4S when ARSB is reduced, leading to sustained phosphorylation of SHP2 targets, including phospho-ERK1/2 and phospho-p38 MAPK. These effects on critical signaling molecules lead to changes in expression of chondroitin sulfate proteoglycan 4 (CSPG4), matrix metalloproteinase (MMP)2, and MMP9 and contribute to the malignant melanoma phenotype. Inverse effects of rhARSB and ARSB siRNA are evident, with rhARSB acting as a tumor suppressor and ARSB siRNA as a tumor promoter. Citation Format: Joanne K. Tobacman, Insug O-Sullivan, Sumit Bhattacharyya. Arylsulfatase B inhibits progression of malignant melanoma by COP1-mediated apoptosis in syngeneic and humanized mouse models [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr C005.