Evidence for a link between histone deacetylation and Ca²+ homoeostasis in sphingosine-1-phosphate lyase-deficient fibroblasts.
Embryonic fibroblasts from S1P (sphingosine-1-phosphate) lyase-deficient mice [Sgpl1-/- MEFs (mouse embryonic fibroblasts)] are characterized by intracellular accumulation of S1P, elevated cytosolic [Ca2+]i and enhanced Ca2+ storage. Since S1P, produced by sphingosine kinase 2 in the nucleus of MCF-7 cells, inhibited HDACs (histone deacetylases) [Hait, Allegood, Maceyka, Strub, Harikumar, Singh, Luo, Marmorstein, Kordula, Milstein et al. (2009) Science 325, 1254-1257], in the present study we analysed whether S1P accumulated in the nuclei of S1P lyase-deficient MEFs and caused HDAC inhibition. Interestingly, nuclear concentrations of S1P were disproportionally elevated in Sgpl1-/- MEFs. HDAC activity was reduced, acetylation of histone 3-Lys9 was increased and the HDAC-regulated gene p21 cyclin-dependent kinase inhibitor was up-regulated in these cells. Furthermore, the expression of HDAC1 and HDAC3 was reduced in Sgpl1-/- MEFs. In wild-type MEFs, acetylation of histone 3-Lys9 was increased by the S1P lyase inhibitor 4-deoxypyridoxine. The non-specific HDAC inhibitor trichostatin A elevated basal [Ca2+]i and enhanced Ca2+ storage, whereas the HDAC1/2/3 inhibitor MGCD0103 elevated basal [Ca2+]i without influence on Ca2+ storage in wild-type MEFs. Overexpression of HDAC1 or HDAC2 reduced the elevated basal [Ca2+]i in Sgpl1-/- MEFs. Taken together, S1P lyase-deficiency was associated with elevated nuclear S1P levels, reduced HDAC activity and down-regulation of HDAC isoenzymes. The decreased HDAC activity in turn contributed to the dysregulation of Ca2+ homoeostasis, particularly to the elevated basal [Ca2+]i, in Sgpl1-/- MEFs.
Institut für Allgemeine Pharmakologie und Toxikologie, Klinikum der Goethe-Universität, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
Katja
K
Ihlefeld
Ralf Frederik
RF
Claas
Alexander
A
Koch
Josef M
JM
Pfeilschifter
Dagmar
D
Meyer Zu Heringdorf
D000107:Acetylation; D000446:Aldehyde-Lyases / Q000235:genetics*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism*; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006706:Homeostasis; D007527:Isoenzymes / Q000378:metabolism; D008246:Lysophospholipids / Q000378:metabolism; D051379:Mice; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism
D006657:Histones; D007527:Isoenzymes; D008246:Lysophospholipids; C060506:sphingosine 1-phosphate; D006655:Histone Deacetylases; D000446:Aldehyde-Lyases; C022649:sphingosine 1-phosphate lyase (aldolase); D013110:Sphingosine; D002118:Calcium