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

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 gamma, but not by RAR alpha or RAR beta, suggesting that RAR gamma 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 gamma target genes that may play a role in this process. Here, we identified and validated carbohydrate sulfotransferase 10 (CHST10) as a novel RAR gamma target gene in S91 cells. The RAR gamma-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 gamma, but not by RAR alpha or RAR beta, thus providing a mechanism for the observed RAR gamma-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 gamma 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 gamma-activating retinoids may present a novel therapeutic strategy to inhibit invasiveness in a subset of melanoma patients. [Cancer Res 2009;69(12):5218-25]