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

摘要

The pleiotropic lipid mediator sphingosine-1-phosphate (SIP) can act intracellularly independently of its cell surface receptors through unknown mechanisms. Sphingosine kinase 2 (SphK2), one of the isoenzymes that generates SIP, was associated with histone H3 and produced SIP that regulated histone acetylation. SIP 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 SIP and link nuclear SIP to epigenetic regulation of gene expression.