Mechanism of regulation and suppression of melanoma invasiveness by novel retinoic acid receptor-gamma 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 RARgamma, but not by RARalpha or RARbeta, suggesting that RARgamma possesses unique and uncharacterized molecular properties. To address this question, DNA microarrays in combination with RAR isoform-specific agonists were employed to identify novel RARgamma target genes that may play a role in this process. Here, we identified and validated carbohydrate sulfotransferase 10 (CHST10) as a novel RARgamma target gene in S91 cells. The RARgamma-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 RARgamma, but not by RARalpha or RARbeta, thus providing a mechanism for the observed RARgamma-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 RARgamma 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 RARgamma-activating retinoids may present a novel therapeutic strategy to inhibit invasiveness in a subset of melanoma patients.
Zhao
Xiansi
X
Cutaneous Biology Research Center, Massachusetts General Hospital, Boston, USA.
Graves
Carole
C
Ames
Sarah J
SJ
Fisher
David E
DE
Spanjaard
Remco A
RA
D001483:Base Sequence; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D004247:DNA; D006801:Humans; D008545:Melanoma / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D008969:Molecular Sequence Data; D009361:Neoplasm Invasiveness; D011401:Promoter Regions, Genetic; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015238:Sulfotransferases / Q000235:genetics* / Q000378:metabolism; D000097768:Retinoic Acid Receptor gamma; D000097811:Carbohydrate Sulfotransferases
D004247:DNA; D018168:Receptors, Retinoic Acid; D015238:Sulfotransferases; D000097768:Retinoic Acid Receptor gamma; C499549:CHST10 protein, human; D000097811:Carbohydrate Sulfotransferases