title: Histone deacetylase inhibitor trichostatin A sustains sodium pervanadate-induced NF-kappaB activation by delaying IkappaBalpha mRNA resynthesis: comparison with tumor necrosis factor alpha.
abstract: NF-kappaB 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) alpha-elicited NF-kappaB activation and delays IkappaBalpha cytoplasmic reappearance. Here, we demonstrated that TSA also prolongs NF-kappaB activation when induced by the insulino-mimetic pervanadate (PV), a tyrosine phosphatase inhibitor that initiates an atypical NF-kappaB signaling. This extension is similarly correlated with delayed IkappaBalpha cytoplasmic reappearance. However, whereas TSA causes a prolonged IKK activity when added to TNFalpha, it does not when added to PV. Instead, quantitative reverse transcriptase-PCR revealed a decrease of ikappabalpha mRNA level after TSA addition to PV stimulation. This synthesis deficit of the inhibitor could explain the sustained NF-kappaB residence in the nucleus. In vivo analysis by chromatin immunoprecipitation assays uncovered that, for PV induction but not for TNFalpha, the presence of TSA provokes several impairments on the ikappabalpha promoter: (i) diminution of RNA Pol II recruitment; (ii) reduced acetylation and phosphorylation of histone H3-Lys(14) and -Ser(10), respectively; (iii) decreased presence of phosphorylated p65-Ser(536); and (iv) reduction of IKKalpha binding. The recruitment of these proteins on the icam-1 promoter, another NF-kappaB-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-kappaB pathway and the targeted promoter in question. This indicates that one overall histone deacetylase role is to inhibit NF-kappaB activation by molecular mechanisms specific of the stimulus and the promoter.
authors.affiliation: Laboratory of Virology and Immunology, GIGA-R, University of Liège, 4000 Liège, Belgium.
authors.forename: Julie
authors.initials: J
authors.lastname: Horion
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Gloire
authors.forename: Nadia
authors.initials: N
authors.lastname: El Mjiyad
authors.forename: Vincent
authors.initials: V
authors.lastname: Quivy
authors.forename: Linda
authors.initials: L
authors.lastname: Vermeulen
authors.forename: Wim
authors.initials: W
authors.lastname: Vanden Berghe
authors.forename: Guy
authors.initials: G
authors.lastname: Haegeman
authors.forename: Carine
authors.initials: C
authors.lastname: Van Lint
authors.forename: Jacques
authors.initials: J
authors.lastname: Piette
authors.forename: Yvette
authors.initials: Y
authors.lastname: Habraken
mesh_terms: D000107:Acetylation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000819:agonists / Q000494:pharmacology*; D006367:HeLa Cells; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000819:agonists / Q000494:pharmacology*; D020672:I-kappa B Proteins / Q000096:biosynthesis*; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000502:physiology; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D012319:RNA Polymerase II / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000819:agonists / Q000494:pharmacology*; D014638:Vanadates / Q000819:agonists / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D012333:RNA, Messenger; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; C076715:pervanadate; D018799:Intercellular Adhesion Molecule-1; D000072000:NF-KappaB Inhibitor alpha; D014638:Vanadates; C012589:trichostatin A; D012319:RNA Polymerase II