Regulation of Histone Acetylation in the Nucleus by Sphingosine-1-Phosphate

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.