Histone deacetylase inhibitors repress macrophage migration inhibitory factor (MIF) expression by targeting MIF gene transcription through a local chromatin deacetylation.
The cytokine macrophage migration inhibitory factor plays a central role in inflammation, cell proliferation and tumorigenesis. Moreover, macrophage migration inhibitory factor levels correlate with tumor aggressiveness and metastatic potential. Histone deacetylase inhibitors are potent antitumor agents recently introduced in the clinic. Therefore, we hypothesized that macrophage migration inhibitory factor would represent a target of histone deacetylase inhibitors. Confirming our hypothesis, we report that histone deacetylase inhibitors of various chemical classes strongly inhibited macrophage migration inhibitory factor expression in a broad range of cell lines, in primary cells and in vivo. Nuclear run on, transient transfection with macrophage migration inhibitory factor promoter reporter constructs and transduction with macrophage migration inhibitory factor expressing adenovirus demonstrated that trichostatin A (a prototypical histone deacetylase inhibitor) inhibited endogenous, but not episomal, MIF gene transcription. Interestingly, trichostatin A induced a local and specific deacetylation of macrophage migration inhibitory factor promoter-associated H3 and H4 histones which did not affect chromatin accessibility but was associated with an impaired recruitment of RNA polymerase II and Sp1 and CREB transcription factors required for basal MIF gene transcription. Altogether, this study describes a new molecular mechanism by which histone deacetylase inhibitors inhibit MIF gene expression, and suggests that macrophage migration inhibitory factor inhibition by histone deacetylase inhibitors may contribute to the antitumorigenic effects of histone deacetylase inhibitors.
Lugrin
Jérôme
J
Infectious Diseases Service, Department of Medicine, Centre Hospitalier Universitaire Vaudois and University of Lausanne, CH-1011 Lausanne, Switzerland.
Ding
Xavier C
XC
Le Roy
Didier
D
Chanson
Anne-Laure
AL
Sweep
Fred C G J
FC
Calandra
Thierry
T
Roger
Thierry
T
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002843:Chromatin / Q000378:metabolism*; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D018922:HL-60 Cells; D006367:HeLa Cells; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D019746:Intramolecular Oxidoreductases / Q000096:biosynthesis*; D008263:Macrophage Migration-Inhibitory Factors / Q000096:biosynthesis*; D051379:Mice; D008807:Mice, Inbred BALB C; D012319:RNA Polymerase II / Q000378:metabolism; D016329:Sp1 Transcription Factor / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*; D020298:U937 Cells
D000970:Antineoplastic Agents; C115163:CREB1 protein, human; D002843:Chromatin; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D008263:Macrophage Migration-Inhibitory Factors; D016329:Sp1 Transcription Factor; C012589:trichostatin A; D012319:RNA Polymerase II; D019746:Intramolecular Oxidoreductases; C515598:MIF protein, human; C076231:Mif protein, mouse