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An atheroprotective transcriptome induced by JQ1 (a BRD4 inhibitor) in human endothelial cells

ABSTRACT: The bromodomain and extra terminal domain (BET) family of proteins, including BRD2, BRD3, and BRD4, play a key role in many cellular processes, including inflammatory gene expression, mitosis, and viral/host interaction by controlling the assembly of histone acetylation-dependent chromatin complexes. Previous studies have shown that multiple BET inhibitors (BETi), including JQ1, have therapeutic effects in cancer and cardiovascular diseases. Some BETi have entered different phases of clinical trials. Pharmacologically, JQ1 functions by displacing BET proteins from chromatin by competitively binding to the acetyl-lysine recognition pocket of BET bromodomains. JQ1 has been used as a chemical probe to investigate the role of BET bromodomains in the transcriptional regulation of cardiovascular diseases. For example, JQ1 has been shown to attenuates inflammation and experimental atherosclerosis (Mol Cell. 2014 Oct 23; 56(2): 219–231.). JQ1 has also recently been shown to reduce EndoMT and cardiac fibrosis (J Mol Cell Cardiol. 2019 Feb;127:83-96.). However, the molecular targets of JQ1 dependent or independent of BRD4 remains unknown. To depict the transcriptomic signature of JQ1 in human endothelial cells, we observed a vasoprotective and atheroprotective transcriptome by JQ1 treatment using genome-wide RNA-seq based transcriptomic profiling. JQ1 is a magic bullet in cardiovascular disease prevention. Further elucidation of new molecular targets of JQ1 will lead to the identification of potentially new therapeutic targets to treat cardiovascular diseases.

ORGANISM(S): Homo sapiens

PROVIDER: GSE137500 | GEO | 2019/11/27

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.

Project description:Targeting the epigenome to modulate gene expression programs driving cancer development has emerged as an exciting avenue for therapeutic intervention. Pharmacological inhibition of the bromodomain and extraterminal (BET) family of chromatin adapter proteins has proven effective in this regard, suppressing growth of diverse cancer types mainly through downregulation of the c-MYC oncogene and its downstream transcriptional program. While initially effective, resistance to BET inhibitors (BETi) typically occurs through mechanisms that reactivate MYC expression. We have previously shown that lung adenocarcinoma (LAC) is inhibited by JQ1 through suppression of FOSL1, suggesting that the epigenetic landscape of tumor cells from different origins and differentiation states influences BETi response. Here, we assessed how these differences affect mechanisms of BETi resistance through the establishment of isogenic pairs of JQ1 sensitive and resistant LAC cell lines. We found that resistance to JQ1 in LAC occurs independent of FOSL1 while MYC levels remain unchanged between resistant cells and their JQ1 treated parental counterparts. Furthermore, while epithelial-mesenchymal transition (EMT) is observed upon resistance, TGF- induced EMT did not confer resistance in JQ1 sensitive LAC lines, suggesting this is a consequence, rather than a driver of BETi resistance in our model systems. Importantly, siRNA knockdown demonstrated that JQ1 resistant cell lines are still dependent on BRD4 expression and we found that phosphorylation of BRD4 is elevated in resistant LACs, identifying casein kinase 2 (CK2) as a candidate protein mediating this effect. Inhibition of CK2, as well as downstream transcriptional targets of phosphorylated BRD4 - including AXL and activators of the PI3K pathway - synergize with JQ1 to inhibit BETi resistant LAC. Overall, this demonstrates that the mechanism of resistance to BETi varies depending on cancer type, with LAC cells developing JQ1 resistance independent of MYC re-activation, and identifying CK2 phosphorylation of BRD4 as a potential target to overcome resistance in this cancer.

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An atheroprotective transcriptome induced by JQ1 (a BRD4 inhibitor) in human endothelial cells

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