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.
Highlights
Signal transducer and activator of transcription STAT5 is an essential regulator of cell differentiation, proliferation and survival [1,2,3]
We showed before that deacetylase inhibitors such as trichostatin A (TSA), suberoylanilide hydroxamic acid (SAHA) or NaB inhibit STAT5 transcriptional activity by preventing recruitment of TBP and RNA polymerase II to the promoter of target genes such as Cis and Osm, at a step following STAT5 binding to DNA [40]
The effect of deacetylase inhibitor treatment on local histone acetylation at the STAT5 target genes was marginal [40,41] and convinced us to consider the possibility that inhibition of STAT5 activity by deacetylase inhibitors targets STAT5 protein rather than chromatin
Summary
Signal transducer and activator of transcription STAT5 is an essential regulator of cell differentiation, proliferation and survival [1,2,3]. A number of inhibitors of the STAT5 pathway have been described, including tyrosine kinase inhibitors targeting JAK family members and small-molecule inhibitors targeting STAT5 phosphorylation or DNA binding activity [34,35,36,37,38,39]. Inhibitors targeting STAT5 transcriptional activity, at a step subsequent to its binding to DNA, have been described. They include deacetylase inhibitors such as trichostatin A (TSA), suberoylanilide hydroxamic acid (SAHA) and sodium butyrate (NaB), initially described by our group, and more recently the bromodomain inhibitor (+)-JQ1 and the natural compound sulforaphane [40,41,42,43]. A number of deacetylase inhibitors are either approved or currently
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