Trichostatin A and 5-aza-2′-deoxycytidine switch S1P from an inhibitor to a stimulator of motility through epigenetic regulation of S1P receptors

The histone deacetylase inhibitor, trichostatin A (TSA), and the DNA methyltransferase inhibitor, 5-aza-2′-deoxycytidine (Aza-dC), induced epigenetic regulation of sphingosine-1-phosphate (S1P) receptors in human melanoma cells, switching S1P from motility inhibitor to stimulator. Quantitative PCR revealed increased expression of S1P1 and S1P3, associated with S1P-induced chemotaxis, and decreased expression of S1P2, associated with motility inhibition. Expression of lysophosphatidic acid (LPA) receptors was less affected. The TSA effect was reversible suggesting no mutational change, and Aza-dC treatment resulted in demethylation of a putative S1P1 promoter. S1P receptors, therefore, appear to be susceptible to epigenetic regulation, accompanied by altered cellular functionality.