BET domain co-regulators in obesity, inflammation and cancer

Belkina, Anna C.; Denis, Gerald V.

doi:10.1038/nrc3256

Cited by 611 publications

(643 citation statements)

References 175 publications

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“…Among these, signal transducer and activator of transcription 3 36 and nuclear factor of activated T cells 12 are key factors promoting cell cycle progression and proliferation. 13 We also pointed out the presence of increased DNA damage and BRD4 overexpression in proximal coronary arteries of . Results are presented as mean of 10 arteries per rat in 6 to 8 rats per group.…”

Section: Discussionmentioning

confidence: 99%

“…12 BRD4 functions as a scaffold for transcription factors at promoters and superenhancers, modulating the chromatin landscape and facilitating transcriptional activation of target genes. 13 Interestingly, BRD4 is also implicated in systemic VRD by triggering proinflammatory endothelial genes, such as IL-6 (interleukin-6), tumor necrosis factor-α, and monocyte chemoattractant protein-1, 14,15 which also stimulate its activation through a feedback loop. 15 Interestingly, these proinflammatory cytokines are upregulated in PAH 16 and are known to cause DNA damage.…”

Section: P Ulmonary Arterial Hypertension (Pah) Is a Vascularmentioning

confidence: 99%

“…17 In cancer, BRD4 is a known trigger of the osteogenic factor Runt-related transcription factor 2 expression, 18,19 which was recently associated with PAH lung abnormalities (including proliferation and calcification), 20 and, interestingly, BRD4 inhibition by JQ1 suppressed vascular calcification/atherogenic processes in a hypercholesterolemic murine model. 15 Furthermore, in addition to promoting DNA damage, 17 atherogenic processes 15 and increased proliferation, 12,13 BRD4 is also associated with inflammation, diabetes mellitus, obesity, and metabolic abnormalities, 13 all playing a role in VRDs, and particularly in coronary artery disease (CAD). 21,22 Heart diseases are the leading global cause of death in both men and women in industrialized countries.…”

Section: P Ulmonary Arterial Hypertension (Pah) Is a Vascularmentioning

confidence: 99%

“…12 BRD4 functions as a scaffold for transcription factors at promoters and superenhancers, modulating the chromatin landscape and facilitating transcriptional activation of target genes. 13 Interestingly, BRD4 is also implicated in systemic VRD by triggering proinflammatory endothelial © 2017 American Heart Association, Inc. Objective-Pulmonary arterial hypertension (PAH) is a vascular disease not restricted to the lungs. Many signaling pathways described in PAH are also of importance in other vascular remodeling diseases, such as coronary artery disease (CAD).…”

Section: P Ulmonary Arterial Hypertension (Pah) Is a Vascularmentioning

confidence: 99%

“…15 Interestingly, these proinflammatory cytokines are upregulated in PAH 16 and are known to cause DNA damage. 9 Thus, BRD4 is a key regulator of the proliferation/apoptosis balance 12,13 by modulating gene expression and plays a critical role in post-DNA damage events. 17 In cancer, BRD4 is a known trigger of the osteogenic factor Runt-related transcription factor 2 expression, 18,19 which was recently associated with PAH lung abnormalities (including proliferation and calcification), 20 and, interestingly, BRD4 inhibition by JQ1 suppressed vascular calcification/atherogenic processes in a hypercholesterolemic murine model.…”

Section: P Ulmonary Arterial Hypertension (Pah) Is a Vascularmentioning

confidence: 99%

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Implication of Inflammation and Epigenetic Readers in Coronary Artery Remodeling in Patients With Pulmonary Arterial Hypertension

Meloche

Lampron

Nadeau

et al. 2017

ATVB

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P ulmonary arterial hypertension (PAH) is a vascularremodeling disease (VRD) first described as an obstructive pathology affecting the distal pulmonary arteries. It is characterized by enhanced inflammation, vasoconstriction, and proliferation/apoptosis imbalance within the arterial wall, leading to increased pulmonary vascular resistance and right ventricular (RV) failure and death. 1 The smooth muscle cells (SMCs) within the pulmonary arterial wall exhibit exaggerated proliferation and resistance to apoptosis. Many groups have studied the underlying mechanisms of this "cancer-like" phenotype to find better ways to treat this deadly disease. The similarities in histological features between PAH and other VRDs suggest common pathogenic mechanisms. We and others have described the implication of the receptor of advanced glycation endproducts, 2-4 the oncoprotein kinase Pim-1 3, 5 and the transcription factor nuclear factor of activated T cells 6,7 in promoting proliferation in remodeling processes occurring in both VRD and PAH. In PAH patients' lung vasculature, these molecular actors are, at least in part, regulated by proinflammatory cytokines, alterations in the miR-223/DNA damage/ Poly[ADP-ribose] polymerase 1/miR-204 axis 8-11 and subsequent overexpression of the epigenetic reader bromodomain protein 4 (BRD4). 12 BRD4 functions as a scaffold for transcription factors at promoters and superenhancers, modulating the chromatin landscape and facilitating transcriptional activation of target genes. 13 Interestingly, BRD4 is also implicated in systemic VRD by triggering proinflammatory endothelial © 2017 American Heart Association, Inc. Objective-Pulmonary arterial hypertension (PAH) is a vascular disease not restricted to the lungs. Many signaling pathways described in PAH are also of importance in other vascular remodeling diseases, such as coronary artery disease (CAD). Intriguingly, CAD is 4× more prevalent in PAH compared with the global population, suggesting a link between these 2 diseases. Both PAH and CAD are associated with sustained inflammation and smooth muscle cell proliferation/ apoptosis imbalance and we demonstrated in PAH that this phenotype is, in part, because of the miR-223/DNA damage/ Poly[ADP-ribose] polymerase 1/miR-204 axis activation and subsequent bromodomain protein 4 (BRD4) overexpression. Interestingly, BRD4 is also a trigger for calcification and remodeling processes, both of which are important in CAD. Thus, we hypothesize that BRD4 activation in PAH influences the development of CAD. Approach and Results-PAH was associated with significant remodeling of the coronary arteries in both human and experimental models of the disease. As observed in PAH distal pulmonary arteries, coronary arteries of patients with PAH also exhibited increased DNA damage, inflammation, and BRD4 overexpression. In vitro, using human coronary artery smooth muscle cells from PAH, CAD and non-PAH-non-CAD patients, we showed that both PAH and CAD smooth muscle cells exhibited increased proliferation and suppres...

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Section: Discussionmentioning

confidence: 99%

Section: P Ulmonary Arterial Hypertension (Pah) Is a Vascularmentioning

confidence: 99%

Section: P Ulmonary Arterial Hypertension (Pah) Is a Vascularmentioning

confidence: 99%

“…12 BRD4 functions as a scaffold for transcription factors at promoters and superenhancers, modulating the chromatin landscape and facilitating transcriptional activation of target genes. 13 Interestingly, BRD4 is also implicated in systemic VRD by triggering proinflammatory endothelial © 2017 American Heart Association, Inc. Objective-Pulmonary arterial hypertension (PAH) is a vascular disease not restricted to the lungs. Many signaling pathways described in PAH are also of importance in other vascular remodeling diseases, such as coronary artery disease (CAD).…”

Section: P Ulmonary Arterial Hypertension (Pah) Is a Vascularmentioning

confidence: 99%

Section: P Ulmonary Arterial Hypertension (Pah) Is a Vascularmentioning

confidence: 99%

See 3 more Smart Citations

Implication of Inflammation and Epigenetic Readers in Coronary Artery Remodeling in Patients With Pulmonary Arterial Hypertension

Meloche

Lampron

Nadeau

et al. 2017

ATVB

View full text Add to dashboard Cite

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Targeting Hippo coactivator YAP1 through BET bromodomain inhibition in esophageal adenocarcinoma

Song

et al. 2020

Molecular Oncology

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Hippo/YAP1 signaling is a major regulator of organ size, cancer stemness, and aggressive phenotype. Thus, targeting YAP1 may provide a novel therapeutic strategy for tumors with high YAP1 expression in esophageal cancer (EC). Chromatin immunoprecipitation (ChiP) and quantitative ChiP-PCR were used to determine the regulation of the chromatin remodeling protein bromodomain-containing protein 4 (BRD4) on YAP1. The role of the bromodomain and extraterminal motif (BET) inhibitor JQ1, an established BRD4 inhibitor, on inhibition of YAP1 in EC cells was dissected using western blot, immunofluorescence, qPCR, and transient transfection.The antitumor activities of BET inhibitor were further examined by variety of functional assays, cell proliferation (MTS), tumorsphere, and ALDH1+ labeling in vitro and in vivo. Here, we show that BRD4 regulates YAP1 expression and transcription. ChiP assays revealed that BRD4 directly occupies YAP1 promoter and that JQ1 robustly blocks BRD4 binding to the YAP1 promoter. Consequently, JQ1 strongly suppresses constitutive or induced YAP1 expression and transcription in EC cells and YAP1/Tead downstream transcriptional activity. Intriguingly, radiation-resistant cells that acquire strong cancer stem cell traits and an aggressive phenotype can be effectively suppressed by JQ1 as assessed by cell proliferation, tumorsphere formation, and reduction in the ALDH1+ cells. Moreover, effects of JQ1 are synergistically amplified by the addition of docetaxel in vitro and in vivo. Our results demonstrate that BRD4 is a critical regulator of Hippo/YAP1 signaling and that BRD4 inhibitor JQ1 represents a new class of inhibitor of Hippo/YAP1 signaling, primarily targeting YAP1 high and therapy-resistant cancer cells enriched with cancer stem cell properties.

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ACC010, a novel BRD4 inhibitor, synergized with homoharringtonine in acute myeloid leukemia with FLT3‐ITD

et al. 2023

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Bromodomain-containing protein 4 (BRD4) inhibitors have been clinically developed to treat acute myeloid leukemia (AML), but their application is limited by the possibility of drug resistance, which is reportedly associated with the activation of the WNT/b-catenin pathway. Meanwhile, homoharringtonine (HHT), a classic antileukemia drug, possibly inhibits the WNT/ b-catenin pathway. In this study, we attempted to combine a novel BRD4 inhibitor (ACC010) and HHT to explore their synergistic lethal effects in treating AML. Here, we found that co-treatment with ACC010 and HHT synergistically inhibited cell proliferation, induced apoptosis, and arrested the cell cycle in FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD)-positive AML cells in vitro, and significantly inhibiting AML progression in vivo. Mechanistically, ACC010 and HHT cooperatively downregulated MYC and inhibited FLT3 activation. Further, when HHT was added, ACC010-resistant cells demonstrated a good synergy. We also extended our study to the mouse BaF3 cell line with FLT3-inhibitorresistant FLT3-ITD/tyrosine kinase domain mutations and AML cells without FLT3-ITD. Collectively, our results suggested that the combination treatment of ACC010 and HHT might be a promising strategy for AML patients, especially those carrying FLT3-ITD.

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BET domain co-regulators in obesity, inflammation and cancer

Cited by 611 publications

References 175 publications

Implication of Inflammation and Epigenetic Readers in Coronary Artery Remodeling in Patients With Pulmonary Arterial Hypertension

Implication of Inflammation and Epigenetic Readers in Coronary Artery Remodeling in Patients With Pulmonary Arterial Hypertension

Targeting Hippo coactivator YAP1 through BET bromodomain inhibition in esophageal adenocarcinoma

ACC010, a novel BRD4 inhibitor, synergized with homoharringtonine in acute myeloid leukemia with FLT3‐ITD

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