Abstract
Arylsulfatase B (ARSB; N-acetylgalactosamine 4-sulfatase) is reduced in several malignancies, but levels in melanoma have not been investigated previously. Experiments were performed in melanoma cell lines to determine ARSB activity and impact on melanoma invasiveness. ARSB activity was reduced ~50% in melanoma cells compared to normal melanocytes. Silencing ARSB significantly increased the mRNA expression of chondroitin sulfate proteoglycan(CSPG)4 and pro-matrix metalloproteinase(MMP)-2, known mediators of melanoma progression. Also, invasiveness and MMP activity increased when ARSB was reduced, and recombinant ARSB inhibited invasiveness and MMP activity. Since the only known function of ARSB is to remove 4-sulfate groups from the N-acetylgalactosamine 4-sulfate residue at the non-reducing end of chondroitin 4-sulfate (C4S) or dermatan sulfate, experiments were performed to determine the transcriptional mechanisms by which expression of CSPG4 and MMP2 increased. Promoter activation of CSPG4 was mediated by reduced binding of galectin-3 to C4S when ARSB activity declined. In contrast, increased pro-MMP2 expression was mediated by increased binding of the non-receptor tyrosine phosphatase SHP2 to C4S. Increased phospho-ERK1,2 resulted from SHP2 inhibition. Combined effects of increased C4S, CSPG4, and MMP2 increased the invasiveness of the melanoma cells, and therapy with recombinant ARSB may inhibit melanoma progression.
Highlights
Malignant melanoma remains one of the most devastating malignancies, with propensity for widespread dissemination and resistance to treatment
We present new mechanistic insights into how melanoma progression can arise in relation to decline in the enzyme arylsulfatase B, with concomitant increase in chondroitin 4-sulfation
CSPG4 was associated with melanoma aggressiveness decades ago, and therapeutic efforts directed at inhibition of CSPG4 have been undertaken
Summary
Malignant melanoma remains one of the most devastating malignancies, with propensity for widespread dissemination and resistance to treatment. The chondroitin sulfate proteoglycan 4 [CSPG4; known as melanoma-associated chondroitin sulfate proteoglycan (MCSP) or neuron-glial antigen 2 (NG2)] was recognized as an important factor in the aggressiveness of melanoma decades ago, but successful intervention focused on CSPG4 has remained elusive [3,4,5]. In addition to the impact of CSPG4 on aggressiveness of melanoma, matrix metalloproteinase (MMP)-2, or gelatinase A, has been associated with increased invasiveness of malignant melanoma, due to effects on the degradation of the extracellular matrix [6,7,8]. Previous work has shown that decline in ARSB and the resulting increase in chondroitin 4-sulfation were associated with transcriptional effects mediated by galectin-3 or by the ubiquitous non-receptor tyrosine phosphatase SHP2 [12,13,14,15,16,17]. Increased expression of versican in human www.impactjournals.com/oncotarget prostate epithelial and stromal cells, hypoxia inducible factor 1-alpha (HIF 1-α) in human colonic and bronchial epithelial cells, and Wnt9A (Wingless-Type MMTV Integration Site Family, Member 9A) in human colonic epithelial cells were reported
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