1. Regulation of histone acetylation in the nucleus by sphingosine-1-phosphate.
- Author
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Hait NC, Allegood J, Maceyka M, Strub GM, Harikumar KB, Singh SK, Luo C, Marmorstein R, Kordula T, Milstien S, and Spiegel S
- Subjects
- Acetylation, Catalytic Domain, Cell Line, Tumor, Cyclin-Dependent Kinase Inhibitor p21 genetics, Cyclin-Dependent Kinase Inhibitor p21 metabolism, Epigenesis, Genetic, Genes, fos, Histone Deacetylase 1, Histone Deacetylase 2, Histone Deacetylase Inhibitors, Histone Deacetylases metabolism, Humans, Lysine metabolism, Nucleosomes metabolism, Phosphotransferases (Alcohol Group Acceptor) genetics, Phosphotransferases (Alcohol Group Acceptor) metabolism, Promoter Regions, Genetic, RNA Interference, Repressor Proteins antagonists & inhibitors, Repressor Proteins metabolism, Sphingosine metabolism, Tetradecanoylphorbol Acetate pharmacology, Cell Nucleus metabolism, Histones metabolism, Lysophospholipids metabolism, Sphingosine analogs & derivatives
- Abstract
The pleiotropic lipid mediator sphingosine-1-phosphate (S1P) can act intracellularly independently of its cell surface receptors through unknown mechanisms. Sphingosine kinase 2 (SphK2), one of the isoenzymes that generates S1P, was associated with histone H3 and produced S1P that regulated histone acetylation. S1P specifically bound to the histone deacetylases HDAC1 and HDAC2 and inhibited their enzymatic activity, preventing the removal of acetyl groups from lysine residues within histone tails. SphK2 associated with HDAC1 and HDAC2 in repressor complexes and was selectively enriched at the promoters of the genes encoding the cyclin-dependent kinase inhibitor p21 or the transcriptional regulator c-fos, where it enhanced local histone H3 acetylation and transcription. Thus, HDACs are direct intracellular targets of S1P and link nuclear S1P to epigenetic regulation of gene expression.
- Published
- 2009
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