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.
Hait
Nitai C
NC
Department of Biochemistry and Molecular Biology and the Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA.
Allegood
Jeremy
J
Maceyka
Michael
M
Strub
Graham M
GM
Harikumar
Kuzhuvelil B
KB
Singh
Sandeep K
SK
Luo
Cheng
C
Marmorstein
Ronen
R
Kordula
Tomasz
T
Milstien
Sheldon
S
Spiegel
Sarah
S
D000107:Acetylation; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D044127:Epigenesis, Genetic; D016762:Genes, fos; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008246:Lysophospholipids / Q000378:metabolism*; D009707:Nucleosomes / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D000099157:Sphingosine Kinase
D050759:Cyclin-Dependent Kinase Inhibitor p21; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D006657:Histones; D008239:Lysine; D008246:Lysophospholipids; D009707:Nucleosomes; D017853:Phosphotransferases (Alcohol Group Acceptor); D012097:Repressor Proteins; D013110:Sphingosine; D013755:Tetradecanoylphorbol Acetate; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate; C110550:HDAC1 protein, human