Sphingosine-1-phosphate (S1P), a lipid mediator, regulates histone acetylation in the nucleus through its intracellular actions. Sphingosine kinase 2 (SphK2), an enzyme that generates S1P, is localized in the nucleus and interacts with histone deacetylases (HDACs) HDAC1 and HDAC2. S1P specifically binds to HDAC1 and HDAC2, inhibiting their enzymatic activity and preventing the removal of acetyl groups from lysine residues in histone tails. SphK2 is enriched at the promoters of genes encoding cyclin-dependent kinase inhibitor p21 and transcriptional regulator c-fos, where it enhances local histone H3 acetylation and transcription. These findings indicate that HDACs are direct intracellular targets of S1P, linking nuclear S1P to epigenetic regulation of gene expression. S1P is a sphingolipid metabolite that regulates various cellular processes. It can act intracellularly independently of its cell surface receptors. SphK2, which is mainly localized in the nucleus, produces S1P and is associated with core histone proteins. SphK2 enhances histone acetylation by inhibiting HDAC activity. S1P and dihydro-S1P, produced by SphK2, inhibit HDAC activity, leading to increased histone acetylation. This process is confirmed by experiments showing that S1P addition to isolated nuclei increases specific histone acetylation. SphK2 depletion reduces nuclear S1P and dihydro-S1P levels, while overexpression of SphK2 enhances histone acetylation. SphK2 is also associated with HDAC1 and HDAC2 in repressor complexes, and its depletion suppresses PMA-induced acetylation of histone H3 at the p21 promoter. SphK2 enhances the transcription of p21 and c-fos genes by increasing histone acetylation. These results indicate that S1P produced in the nucleus by SphK2 regulates histone acetylation and gene expression. S1P binds to HDAC1 and HDAC2, inhibiting their activity. SphK2 is a key enzyme in nuclear sphingolipid metabolism, and its activity is regulated by external signals such as PMA. S1P signaling through SphK2 in the nucleus influences chromatin states and gene transcription, linking nuclear S1P to epigenetic regulation. SphK2 plays a crucial role in maintaining the balance of histone acetylation and gene expression, highlighting its importance in cellular processes.Sphingosine-1-phosphate (S1P), a lipid mediator, regulates histone acetylation in the nucleus through its intracellular actions. Sphingosine kinase 2 (SphK2), an enzyme that generates S1P, is localized in the nucleus and interacts with histone deacetylases (HDACs) HDAC1 and HDAC2. S1P specifically binds to HDAC1 and HDAC2, inhibiting their enzymatic activity and preventing the removal of acetyl groups from lysine residues in histone tails. SphK2 is enriched at the promoters of genes encoding cyclin-dependent kinase inhibitor p21 and transcriptional regulator c-fos, where it enhances local histone H3 acetylation and transcription. These findings indicate that HDACs are direct intracellular targets of S1P, linking nuclear S1P to epigenetic regulation of gene expression. S1P is a sphingolipid metabolite that regulates various cellular processes. It can act intracellularly independently of its cell surface receptors. SphK2, which is mainly localized in the nucleus, produces S1P and is associated with core histone proteins. SphK2 enhances histone acetylation by inhibiting HDAC activity. S1P and dihydro-S1P, produced by SphK2, inhibit HDAC activity, leading to increased histone acetylation. This process is confirmed by experiments showing that S1P addition to isolated nuclei increases specific histone acetylation. SphK2 depletion reduces nuclear S1P and dihydro-S1P levels, while overexpression of SphK2 enhances histone acetylation. SphK2 is also associated with HDAC1 and HDAC2 in repressor complexes, and its depletion suppresses PMA-induced acetylation of histone H3 at the p21 promoter. SphK2 enhances the transcription of p21 and c-fos genes by increasing histone acetylation. These results indicate that S1P produced in the nucleus by SphK2 regulates histone acetylation and gene expression. S1P binds to HDAC1 and HDAC2, inhibiting their activity. SphK2 is a key enzyme in nuclear sphingolipid metabolism, and its activity is regulated by external signals such as PMA. S1P signaling through SphK2 in the nucleus influences chromatin states and gene transcription, linking nuclear S1P to epigenetic regulation. SphK2 plays a crucial role in maintaining the balance of histone acetylation and gene expression, highlighting its importance in cellular processes.