Deacetylase inhibitors repress STAT5-mediated transcription by interfering with bromodomain and extra-terminal (BET) protein function

Nucleic Acids Research
Sophia PinzAnne Rascle

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...Continue Reading

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Citations

Jan 26, 2016·Cell Reports·Lauren E SurfaceLaurie A Boyer
Mar 15, 2016·Biochemical and Biophysical Research Communications·Olivier GoupilleStany Chrétien
Oct 20, 2015·Epigenomics·Peter O BrookAndrew L Durham
Aug 6, 2016·Cellular and Molecular Life Sciences : CMLS·Dequina A NicholasGerald V Denis
Jan 21, 2017·Kidney International·Maria FragiadakiAlbert C M Ong
Jun 8, 2017·Genes·Manpreet KalkatLinda Z Penn
Mar 13, 2019·Journal of Leukocyte Biology·Vijaykumar S MeliWendy F Liu
Jul 23, 2020·Expert Opinion on Investigational Drugs·Helen T ChifotidesSrdan Verstovsek
Jan 20, 2021·Signal Transduction and Targeted Therapy·Nian WangRui Kang
Jun 10, 2021·European Journal of Medicinal Chemistry·Ying-Chao DuanYuan-Yuan Guan
Apr 23, 2020·Journal of Medicinal Chemistry·Tingting LiuGuiyun Duan

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Methods Mentioned

BETA
acetylation
histone acetylation
nuclear translocation
gel filtration
immunoprecipitation
ChIP
transfection
FCS
transfections
PCR

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