Résumé
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 iκbα promoter: (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.