Nuclear SphK2 and S1P regulate Stat3 acetylation and transcriptional activity

Activation of nuclear SphK2 produced intracellular S1P, which promotes histone acetylation by directly binding to and inhibiting HDAC1, thereby de‐repressing p21 and cfos expression (Science, 2009). Many acetylated non‐histone proteins targeted for deacetylation by HDACs are the products of oncogenes or tumor‐suppressor genes. For example, reversible acetylation of the transcription factor, STAT3, has been proposed to regulate its dimerization and transcriptional activity. In agreement, we found that TSA, a pan HDAC inhibitor, increased STAT3 acetylation and enhanced its DNA binding and transcriptional activities, suggesting that HDACs may play an important role in regulating STAT3 acetylation and activation. We have now investigated the possibility that inhibition of HDACs by S1P also regulates STAT3 acetylation and its transcriptional activity. Moreover, we were able to detect association of endogenous STAT3 with HDAC1 and SphK2 and showed that overexpression of SphK2, but not catalytically inactive SphK2, enhanced STAT3 acetylation at lysine 685, a site known to be important for its dimerization and transcriptional activity. S1P also increased STAT3 DNA binding activity. Finally, siSphK2 decreased basal and IL6‐stimulated STAT3 acetylation as well as transcription of IL6‐stimulated STAT3 target genes involved in cell growth, cell survival, and apoptosis.