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 S1P(1) and S1P(3), associated with S1P-induced chemotaxis, and decreased expression of S1P(2), 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 S1P(1) promoter. S1P receptors, therefore, appear to be susceptible to epigenetic regulation, accompanied by altered cellular functionality.
Koh
Eunjin
E
Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-1500, USA. kohe@mail.nih.gov
Bandle
Russell
R
Clair
Timothy
T
Roberts
David D
DD
Stracke
Mary L
ML
D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D019175:DNA Methylation; D000077209:Decitabine; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008246:Lysophospholipids / Q000494:pharmacology*; D008545:Melanoma / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D049312:Receptors, Lysophospholipid; D049349:Receptors, Lysosphingolipid / Q000235:genetics*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology
C108381:GEMIN2 protein, human; D006877:Hydroxamic Acids; D008246:Lysophospholipids; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D049312:Receptors, Lysophospholipid; D049349:Receptors, Lysosphingolipid; C060506:sphingosine 1-phosphate; C012589:trichostatin A; D000077209:Decitabine; D001374:Azacitidine; D013110:Sphingosine