Nuclear matrix contains glycophospholipids, SLs, and cholesterol. In particular, SLs include SM, the most abundant nuclear SL, Cer, C1P, Sph, S1P, and gangliosides [
166,
167]. A recent study on intra-nuclear SM localization, obtained by using neutral sphingomyelinase conjugated to colloidal gold particles, revealed that SM is preferentially localized within the peri-chromatin region [
168]. Moreover, Scassellati et al. (2010) [
168] suggested the presence of SM at the nucleolus. SM has also been found associated with RNA in a complex that affords protection from RNAses. The presence of SM and the enzymes responsible for its metabolism in nuclear membranes as well as in the nuclear matrix may suggest that the signaling starting from SM degradation contributes to regulate not only nuclear membrane properties, such as those correlated to membrane fluidity, but also intranuclear functions. Moreover, other enzymes necessary for the autonomous metabolism of Cer and Sph are present into the nucleus [
161], opening interesting perspectives for SLs peculiar nuclear functions, such as DNA duplication and regulation of chromatin remodeling and gene expression/transcription (reviewed in [
169,
170]).
SphK2/S1P signaling axis in the nucleus and its role in gene regulation via epigenetic mechanism(s) is an emerging field of the research. In the nucleus, S1P is less abundant compared to Sph and Cer, but, as reported in several studies, its level is strictly regulated. For instance, S1P content increases after infection with
P. aeruginosa in epithelial cells and in embryonic fibroblasts obtained from S1PL1 knockout mice (sgpl1
−/−) [
171]. An accumulation of the bioactive lipid also occurs after inhibition of S1PL by THI (2-acetyl-5- tetrahydroxybutl imidazole) [
172]. Increased nuclear S1P level is reported in MCF-7 cells overexpressing SphK2, whereas reduced level occurs in down-regulated SphK2 cells [
59]. Similarly, pharmacological inhibition of SphK2 activity with its rather specific inhibitor, ABC294640, reduces the amount of S1P in the nucleus [
173]. In addition, SphK2 can promote the phosphorylation of fingolimod (FTY720) and its accumulation either in the cytoplasm or in the nuclei of mouse embryonic fibroblasts, SH-SY7Y neuroblastoma, and hippocampal cells [
174,
175]. Notably, the localization and the expression of selective S1PRs has been correlated with tumor progression and prognosis. In fact, elevated level of cytoplasmic S1PR1 and nuclear S1PR2/S1PR3 expression are associated with breast cancer survival [
176]. Moreover, a role for S1PR4 in breast cancer prognosis has been reported [
65]. Finally, it has been documented that, in mammalian cells, S1PR5 co-localizes with SphK1/2 in the centrosome, a site for active GTP-GDP cycling involving G(i) and tubulin, which are required for spindle pole organization [
64]. This finding may suggest a function for S1PR5 as a ligand-activated guanine nucleotide exchanger factor (GEF) in regulating cellular division. Despite these reports, further studies are necessary to identify the exact role of elevated nuclear S1P or S1P analogue signaling in the appearance and progression of diseases. Hait and collegues (2009) [
59] reported for the first time that S1P can associate with histone H3 and control the binding of acetyl groups to lysine residues within histone tails through HDAC1/HDAC2 regulation [
59,
175]. In particular, nuclear SphK2/phospho-SphK2 and S1P co-immunoprecipitated with HDAC1/2 leading to increased histone acetylation at several lysine residues of histone H3, as reported in MCF-7 and MLE-12 cells, and mouse embryonic fibroblasts [
72,
173,
174,
175]. Therefore, HDACs are direct intracellular targets of SphK2/S1P axis and SphK2 is a part of repressor complex and support the involvement of S1P in the epigenetic regulation of gene expression. In general, in mammalian cells, the chromatin remodeling is the result of two major co-repressor complexes Sin3a, and NuRD/Mi2 [
177,
178]. It has been demonstrated that SphK2 and the active phospho-SphK2 associate with HDAC1/2 as part of these two co-repressor complexes. The formation of these complexes at the promoter of genes encoding pro-inflammatory cytokines [
173], is crucial for the ability of SphK2 to modulate inflammation and tissue injury. For instance, it has been reported that genetic deletion of SphK2, but not of SphK1, protected mouse against
P. aeruginosa mediated lung inflammation and pro-inflammatory cytokines secretion (i.e., IL-6 and TNF-α) [
179]. Moreover, in epithelial cells SphK2/S1P activation is able to control the cytokine secretion through HDAC1/2 [
179]. Although it has been shown that DHAC inhibitors (i.e., trichostatin A) and unlabeled S1P compete with [
32P] labelled S1P [
59], the exact molecular mechanism(s) of S1P-mediated inhibition of HDAC1/2 activity and the significance of this regulation in vivo remains to be carefully investigated.