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Mechanism of Regulation and Suppression of Melanoma Invasiveness by Novel Retinoic Acid Receptor- Target Gene Carbohydrate Sulfotransferase 10

¹ Cutaneous Biology Research Center, Massachusetts General Hospital; ² Departments of Otolaryngology and Biochemistry, Cancer Research Center, Boston University School of Medicine, Boston, Massachusetts

Requests for reprints: Remco A. Spanjaard, Departments of Otolaryngology and Biochemistry, Cancer Research Center, Boston University School of Medicine, 72 East Concord Street R-903, Boston, MA 02118. Phone: 617-638-7934; Fax: 617-638-5837; E-mail: rspan{at}bu.edu.

Key Words: promoter • gene expression • S91 • HNK-1 ST • differentiation

Retinoic acid (RA) induces growth arrest and differentiation of S91 murine melanoma cells and serves as a valuable model for this disease. RA acts through activation of RA receptors (RAR), which are members of the nuclear receptor superfamily of ligand-inducible transcription factors. Interestingly, differentiation is mediated by RAR, but not by RAR or RARβ, suggesting that RAR possesses unique and uncharacterized molecular properties. To address this question, DNA microarrays in combination with RAR isoform-specific agonists were employed to identify novel RAR target genes that may play a role in this process. Here, we identified and validated carbohydrate sulfotransferase 10 (CHST10) as a novel RAR target gene in S91 cells. The RAR-inducible CHST10 promoter was obtained, and two atypical, independently functioning RA response elements were identified in a 425 bp region. Surprisingly, this fragment is bound by RAR, but not by RAR or RARβ, thus providing a mechanism for the observed RAR-specific regulation. CHST10 is a sulfotransferase that forms HNK-1 glycan on neural cell adhesion proteins and glycolipids, and HNK-1 is thought to modulate cell adhesion and possibly metastasis. We show that CHST10 is also regulated by RAR in a significant subset of human melanoma cells, and three-dimensional cell culture migration assays suggest that CHST10 functions as a suppressor of invasiveness, but not proliferation, in these cells. Induction of CHST10 by RAR-activating retinoids may present a novel therapeutic strategy to inhibit invasiveness in a subset of melanoma patients. [Cancer Res 2009;69(12):5218–25]