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Determining the impact of the Bromodomain and extra-terminal inhibitor JQ1 on the GATA2 cistrome in castrate-resistant prostate cancer

ABSTRACT: To determine the impact of the Bromodomain and extra-terminal (BET) inhibitor JQ1 on the GATA2 cistrome in castrate-resistant prostate cancer we performed GATA2 ChIP-seq in the presence and absence of JQ1 and assessed differential binding upon JQ1 treatment for 24 hours. We first determined the GATA2 cistrome using our GATA2 ChIP-seq data. Overlapping this with previously published ChIP-seq data for the BET family of proteins (Asangani et al., 2014), we identified a substantial proportion of GATA2 genomic binding sites which are co-occupied by a BET protein. We then quantified differential binding of GATA2 upon JQ1 treatment genome-wide.

ORGANISM(S): Homo sapiens

PROVIDER: GSE125236 | GEO | 2019/01/17

REPOSITORIES: GEO

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Project description:Selective bromodomains inhibitors block the interaction between diverse bromodomains and extraterminal domains (BET) proteins and acetylated proteins. These inhibitors have shown beneficial effects in cancers malignancies and experimental inflammation in mouse models, but data on renal diseases are scarce. We have investigated the effect of the BET proteins inhibitor JQ1 in a mice model of unilateral ureteral obstruction. Treatment with JQ1 diminished renal damage, the presence of inflammatory cell infiltration and the upregulation of proinflammatory genes. The in vitro evaluation of JQ1 on TNF-Î± inducible genes in renal cells showed that BET inhibition modulated several biological processes, including inflammation or immune response. Moreover, gene-silencing experiments showed that BRD4 regulates several proinflammatory genes (IL-6, CCL-2 and CCL-5) and chromatin immunoprecipitation techniques demonstrated that BRD4 specifically binds to acetylated histone H3 in the promoter region of those genes. The nuclear factor-ï«B (NF-ï«B) pathway regulates renal inflammation. The RelA NF-ï«B subunit is activated by acetylation of lysine 310. In damaged kidneys and in TNF-Î±-treated renal cells, JQ1 blocked the nuclear translocation of RelA/NF-ï«B and NF-ï«B-mediated gene expression. Additionally, obstructed kidneys showed an activation of the Th17 immune response, which was diminished by JQ1 treatment. Our results demonstrate that the BET inhibition decreases renal inflammation by 3 independent mechanisms: 1) chromatin remodelling in the promoter regions of specific genes, 2) blocking NF-ï«B pathway activation, and 3) modulating the Th17 immune response. These results suggest that BET inhibitors could have important therapeutic applications in inflammatory renal diseases. HK2 cell line was treated with JQ1 or its enantiomer JQ1(-) (500nM) for 1 hour before stimulation or not with TNF-Î± (5ng/ml) for additional 3h. We analized the genes up- and down-regulated by TNF-Î± vs unstimulated cells, and further the genes downregulated or unaffected by JQ1 compared to the cells treated with the enantiomer (-) JQ1.

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Determining the impact of the Bromodomain and extra-terminal inhibitor JQ1 on the GATA2 cistrome in castrate-resistant prostate cancer

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