title: Deacetylase inhibitors repress STAT5-mediated transcription by interfering with bromodomain and extra-terminal (BET) protein function.
abstract: Signal transducer and activator of transcription STAT5 is essential for the regulation of proliferation and survival genes. Its activity is tightly regulated through cytokine signaling and is often upregulated in cancer. We showed previously that the deacetylase inhibitor trichostatin A (TSA) inhibits STAT5-mediated transcription by preventing recruitment of the transcriptional machinery at a step following STAT5 binding to DNA. The mechanism and factors involved in this inhibition remain unknown. We now show that deacetylase inhibitors do not target STAT5 acetylation, as we initially hypothesized. Instead, they induce a rapid increase in global histone acetylation apparently resulting in the delocalization of the bromodomain and extra-terminal (BET) protein Brd2 and of the Brd2-associated factor TBP to hyperacetylated chromatin. Treatment with the BET inhibitor (+)-JQ1 inhibited expression of STAT5 target genes, supporting a role of BET proteins in the regulation of STAT5 activity. Accordingly, chromatin immunoprecipitation demonstrated that Brd2 is associated with the transcriptionally active STAT5 target gene Cis and is displaced upon TSA treatment. Our data therefore indicate that Brd2 is required for the proper recruitment of the transcriptional machinery at STAT5 target genes and that deacetylase inhibitors suppress STAT5-mediated transcription by interfering with Brd2 function.
authors.affiliation: Stat5 Signaling Research Group, Institute of Immunology, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: Sophia
authors.initials: S
authors.lastname: Pinz
authors.affiliation: Stat5 Signaling Research Group, Institute of Immunology, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: Samy
authors.initials: S
authors.lastname: Unser
authors.affiliation: Stat5 Signaling Research Group, Institute of Immunology, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Buob
authors.affiliation: Stat5 Signaling Research Group, Institute of Immunology, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Fischer
authors.affiliation: Stat5 Signaling Research Group, Institute of Immunology, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: Belinda
authors.initials: B
authors.lastname: Jobst
authors.affiliation: Stat5 Signaling Research Group, Institute of Immunology, University of Regensburg, 93053 Regensburg, Germany anne.rascle@klinik.uni-regensburg.de.
authors.forename: Anne
authors.initials: A
authors.lastname: Rascle
mesh_terms: D000107:Acetylation; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D018274:Electroporation; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D050799:STAT5 Transcription Factor / Q000737:chemistry / Q000502:physiology*; D017386:Sequence Homology, Amino Acid; D014158:Transcription, Genetic / Q000187:drug effects* / Q000502:physiology
chemical_list: D056572:Histone Deacetylase Inhibitors; D006657:Histones; D050799:STAT5 Transcription Factor