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

Area of Science:

• Molecular Biology
• Gene Regulation
• Cancer Biology

Background:

• Signal transducer and activator of transcription 5 (STAT5) is crucial for cell proliferation and survival genes, with dysregulation common in cancer.
• Trichostatin A (TSA), a deacetylase inhibitor, was previously shown to inhibit STAT5 transcription by blocking machinery recruitment post-DNA binding.
• The precise mechanism and factors mediating TSA's inhibition of STAT5 were previously unknown.

Purpose of the Study:

• To elucidate the mechanism by which deacetylase inhibitors, such as TSA, suppress STAT5-mediated transcription.
• To identify the specific factors involved in the inhibition of STAT5 transcriptional activity by deacetylase inhibitors.

Main Methods:

• Investigated the effect of deacetylase inhibitors on STAT5 acetylation and global histone acetylation.
• Examined the localization of bromodomain and extra-terminal (BET) proteins, specifically Brd2 and TBP, following TSA treatment.
• Utilized the BET inhibitor (+)-JQ1 to assess the role of BET proteins in STAT5 target gene expression.
• Performed chromatin immunoprecipitation (ChIP) to determine Brd2 association with the STAT5 target gene Cis.

Main Results:

• Deacetylase inhibitors do not directly target STAT5 acetylation but increase global histone acetylation.
• Increased histone acetylation leads to the delocalization of BET protein Brd2 and TBP from chromatin.
• Inhibition of BET proteins with (+)-JQ1 reduces STAT5 target gene expression.
• Brd2 is associated with the active STAT5 target gene Cis and is displaced upon TSA treatment.

Conclusions:

• Brd2 is essential for recruiting the transcriptional machinery to STAT5 target genes.
• Deacetylase inhibitors suppress STAT5-mediated transcription by interfering with Brd2 function, leading to impaired transcriptional machinery recruitment.