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

Overview

Journal Science

Specialty Science

Date 2009 Sep 5

PMID 19729656

Citations 554

Authors

Nitai C Hait

Jeremy Allegood

Michael Maceyka

Graham M Strub

Kuzhuvelil B Harikumar

Sandeep K Singh

Cheng Luo

Ronen Marmorstein

Tomasz Kordula

Sheldon Milstien

Sarah Spiegel

Affiliations

Soon will be listed here.

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.

Citing Articles

Melanophilin inhibit the growth and lymph node metastasis of triple negative breast cancer via the NONO-SPHK1-S1P axis.

Yao X, Yuen T, Qingchuan C, Jianjun Z, Yefu L, Shulan S J Transl Med. 2025; 23(1):284.

PMID: 40050909 PMC: 11887221. DOI: 10.1186/s12967-025-06240-9.

Endothelial OX40 activation facilitates tumor cell escape from T cell surveillance through S1P/YAP-mediated angiogenesis.

He B, Zhao R, Zhang B, Pan H, Liu J, Huang L J Clin Invest. 2025; 135(5).

PMID: 40026246 PMC: 11870743. DOI: 10.1172/JCI186291.

Lipid Metabolism in Breast Cancer: From Basic Research to Clinical Application.

Huang X, Liu B, Shen S Cancers (Basel). 2025; 17(4).

PMID: 40002245 PMC: 11852908. DOI: 10.3390/cancers17040650.

Sphingosine-1-Phosphate Metabolic Pathway in Cancer: Implications for Therapeutic Targets.

Rufail M, Bassi R, Giussani P Int J Mol Sci. 2025; 26(3).

PMID: 39940821 PMC: 11817292. DOI: 10.3390/ijms26031056.

Sphingosine kinase 1 inhibition aggravates vascular smooth muscle cell calcification.

Razazian M, Bahiraii S, Jannat I, Tiffner A, Beilhack G, Levkau B Pflugers Arch. 2025; .

PMID: 39899071 DOI: 10.1007/s00424-025-03068-6.

References

Minucci S, Pelicci P . Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer. 2006; 6(1):38-51. DOI: 10.1038/nrc1779. View

Chun J, Rosen H . Lysophospholipid receptors as potential drug targets in tissue transplantation and autoimmune diseases. Curr Pharm Des. 2006; 12(2):161-71. DOI: 10.2174/138161206775193109. View

Irvine R . Nuclear lipid signalling. Nat Rev Mol Cell Biol. 2003; 4(5):349-60. DOI: 10.1038/nrm1100. View

Liu H, Sugiura M, Nava V, Edsall L, Kono K, Poulton S . Molecular cloning and functional characterization of a novel mammalian sphingosine kinase type 2 isoform. J Biol Chem. 2000; 275(26):19513-20. DOI: 10.1074/jbc.M002759200. View

Albi E, Lazzarini R, Magni M . Phosphatidylcholine/sphingomyelin metabolism crosstalk inside the nucleus. Biochem J. 2007; 410(2):381-9. DOI: 10.1042/BJ20070758. View

Cocco L, Maraldi N, Manzoli F, Gilmour R, Lang A . Phospholipid interactions in rat liver nuclear matrix. Biochem Biophys Res Commun. 1980; 96(2):890-8. DOI: 10.1016/0006-291x(80)91439-4. View

ODonnell A, Yang S, Sharrocks A . MAP kinase-mediated c-fos regulation relies on a histone acetylation relay switch. Mol Cell. 2008; 29(6):780-5. PMC: 3574235. DOI: 10.1016/j.molcel.2008.01.019. View

Spiegel S, Milstien S . Sphingosine-1-phosphate: an enigmatic signalling lipid. Nat Rev Mol Cell Biol. 2003; 4(5):397-407. DOI: 10.1038/nrm1103. View

Yang X, Seto E . The Rpd3/Hda1 family of lysine deacetylases: from bacteria and yeast to mice and men. Nat Rev Mol Cell Biol. 2008; 9(3):206-18. PMC: 2667380. DOI: 10.1038/nrm2346. View

10.

Spiegel S, Milstien S . Functions of the multifaceted family of sphingosine kinases and some close relatives. J Biol Chem. 2006; 282(4):2125-9. DOI: 10.1074/jbc.R600028200. View

11.

Dokmanovic M, Clarke C, Marks P . Histone deacetylase inhibitors: overview and perspectives. Mol Cancer Res. 2007; 5(10):981-9. DOI: 10.1158/1541-7786.MCR-07-0324. View

12.

Mitra P, Payne S, Milstien S, Spiegel S . A rapid and sensitive method to measure secretion of sphingosine-1-phosphate. Methods Enzymol. 2007; 434:257-64. DOI: 10.1016/S0076-6879(07)34014-7. View

13.

Lagger G, OCarroll D, Rembold M, Khier H, Tischler J, Weitzer G . Essential function of histone deacetylase 1 in proliferation control and CDK inhibitor repression. EMBO J. 2002; 21(11):2672-81. PMC: 126040. DOI: 10.1093/emboj/21.11.2672. View

14.

Haberland M, Montgomery R, Olson E . The many roles of histone deacetylases in development and physiology: implications for disease and therapy. Nat Rev Genet. 2008; 10(1):32-42. PMC: 3215088. DOI: 10.1038/nrg2485. View

15.

Sankala H, Hait N, Paugh S, Shida D, Lepine S, Elmore L . Involvement of sphingosine kinase 2 in p53-independent induction of p21 by the chemotherapeutic drug doxorubicin. Cancer Res. 2007; 67(21):10466-74. DOI: 10.1158/0008-5472.CAN-07-2090. View

16.

Ding G, Sonoda H, Yu H, Kajimoto T, Goparaju S, Jahangeer S . Protein kinase D-mediated phosphorylation and nuclear export of sphingosine kinase 2. J Biol Chem. 2007; 282(37):27493-27502. DOI: 10.1074/jbc.M701641200. View

17.

Hait N, Bellamy A, Milstien S, Kordula T, Spiegel S . Sphingosine kinase type 2 activation by ERK-mediated phosphorylation. J Biol Chem. 2007; 282(16):12058-65. DOI: 10.1074/jbc.M609559200. View

18.

Gui C, Ngo L, Xu W, Richon V, Marks P . Histone deacetylase (HDAC) inhibitor activation of p21WAF1 involves changes in promoter-associated proteins, including HDAC1. Proc Natl Acad Sci U S A. 2004; 101(5):1241-6. PMC: 337037. DOI: 10.1073/pnas.0307708100. View

19.

Finnin M, Donigian J, Cohen A, Richon V, Rifkind R, Marks P . Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors. Nature. 1999; 401(6749):188-93. DOI: 10.1038/43710. View

20.

Schwab S, Cyster J . Finding a way out: lymphocyte egress from lymphoid organs. Nat Immunol. 2007; 8(12):1295-301. DOI: 10.1038/ni1545. View