Histone deacetylase inhibitor trichostatin A sustains sodium pervanadate-induced NF-κB activation by delaying IκBα mRNA resynthesis: Comparison with tumor necrosis factor α

Abstract

NF-κB is a crucial transcription factor tightly regulated by protein interactions and post-translational modifications, like phosphorylation and acetylation. A previous study has shown that trichostatin A (TSA), a histone deacetylase inhibitor, potentiates tumor necrosis factor (TNF) α-elicited NF-κB activation and delays IκBα cytoplasmic reappearance. Here, we demonstrated that TSA also prolongs NF-κB activation when induced by the insulino-mimetic pervanadate (PV), a tyrosine phosphatase inhibitor that initiates an atypical NF-κB signaling. This extension is similarly correlated with delayed IκBα cytoplasmic reappearance. However, whereas TSA causes a prolonged IKK activity when added to TNFα, it does not when added to PV. Instead, quantitative reverse transcriptase-PCR revealed a decrease of iκbα mRNA level after TSA addition to PV stimulation. This synthesis deficit of the inhibitor could explain the sustained NF-κB residence in the nucleus. In vivo analysis by chromatin immunoprecipitation assays uncovered that, for PV induction but not for TNFα, the presence of TSA provokes several impairments on the iκbαpromoter: (i) diminution of RNA Pol II recruitment; (ii) reduced acetylation and phosphorylation of histone H3-Lys14 and -Ser10, respectively; (iii) decreased presence of phosphorylated p65-Ser536; and (iv) reduction of IKKα binding. The recruitment of these proteins on the icam-1 promoter, another NF-κB-regulated gene, is not equally affected, suggesting a promoter specificity of PV with TSA stimulation. Taken together, these data suggest that TSA acts differently depending on the NF-κB pathway and the targeted promoter in question. This indicates that one overall histone deacetylase role is to inhibit NF-κB activation by molecular mechanisms specific of the stimulus and the promoter. © 2007 by The American Society for Biochemistry and Molecular Biology, Inc.