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Science 325 (5945): 1254-1257

Copyright © 2009 by the American Association for the Advancement of Science

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

Nitai C. Hait,1 Jeremy Allegood,1 Michael Maceyka,1 Graham M. Strub,1 Kuzhuvelil B. Harikumar,1 Sandeep K. Singh,1 Cheng Luo,2,3 Ronen Marmorstein,2 Tomasz Kordula,1 Sheldon Milstien,4 Sarah Spiegel1,*

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.

1 Department of Biochemistry and Molecular Biology and the Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA.
2 The Wistar Institute and Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104, USA.
3 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P. R. China.
4 National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA.

* To whom correspondence should be addressed. E-mail: sspiegel{at}vcu.edu

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