Mechanisms of human γ-globin transcriptional induction by apicidin involves p38 signaling to chromatin

Abstract

Histone deacetylase (HDAC) inhibitors are one of promising drugs to induce fetal hemoglobin (HbF) for treatment of sickle cell disease (SCD) and β-thalassemia. The HDAC inhibitor apicidin was recently reported as a powerful inducer of HbF via a mechanism involving p38 signaling. In this study, we further investigated the signaling effects on the transcriptional activation of γ-globin gene. First, we compared histone 3 (H3) acetylation patterns of ∼70 kb β-globin loci in K562 erythroid versus HeLa cells upon apicidin treatment by chromatin immunoprecipitation assays. The results showed that the level of H3 acetylation was globally increased from the LCR to the promoter of γ-globin gene in K562 cells, but not in non-erythroid, HeLa cells. Inhibition of p38 signaling blocks the effects of apicidin-induced γ-globin expression and H3 acetylation. In parallel, we assessed the recruitment of transcriptional complex to β-globin locus following apicidin treatment. The binding of GATA-1, Sp1 and RNA polymerase II (pol II) were observed to increase over several regulatory regions of β-globin locus. Inhibitor study revealed that p38 pathway was not involved in their recruitments by apicidin. Collectively, our results provide a molecular basis to elucidate the underlying mechanisms involving p38 signaling pathway in the inducement of γ-globin transcriptional expression by apicidin.