BRD4 inhibition for the treatment of pathological organ fibrosis

Stratton, Matthew S.; Haldar, Saptarsi M.; McKinsey, Timothy A.

doi:10.12688/f1000research.11339.1

Cited by 50 publications

(46 citation statements)

References 44 publications

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“…JQ1 derivatives are a new class of drugs in cancer therapy now under investigation in human clinical trials (Berthon et al, ; von Schaper, ). Recent studies also have demonstrated that BET inhibitors exhibit profound anti‐fibrotic effects in rodent models of organ failure (Ding et al, ; Duan et al, ; Stratton et al, ). These studies build on the mechanistic rationale that BET inhibitors inhibit the binding of BRD4, which is a nodal, positive regulator of pro‐fibrotic gene expression, and promote extracellular matrix (ECM) deposition and tissue remodeling (Stratton et al, ).…”

Section: Discussionmentioning

confidence: 99%

Elevated H3K27ac in aged skeletal muscle leads to increase in extracellular matrix and fibrogenic conversion of muscle satellite cells

Zhou

et al. 2019

Aging Cell

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Epigenetic alterations occur in various cells and tissues during aging, but it is not known if such alterations are also associated with aging in skeletal muscle. Here, we examined the changes of a panel of histone modifications and found H3K27ac (an active enhancer mark) is markedly increased in aged human skeletal muscle tissues. Further analyses uncovered that the H3K27ac increase and enhancer activation are associated with the up‐regulation of extracellular matrix (ECM) genes; this may result in alteration of the niche environment for skeletal muscle stem cells, also called satellite cells (SCs), which causes decreased myogenic potential and fibrogenic conversion of SCs. In mice, treatment of aging muscles with JQ1, an inhibitor of enhancer activation, inhibited the ECM up‐regulation and fibrogenic conversion of SCs and restored their myogenic differentiation potential. Altogether, our findings not only uncovered a novel aspect of skeletal muscle aging that is associated with enhancer remodeling but also implicated JQ1 as a potential treatment approach for restoring SC function in aging muscle.

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Section: Discussionmentioning

confidence: 99%

Elevated H3K27ac in aged skeletal muscle leads to increase in extracellular matrix and fibrogenic conversion of muscle satellite cells

Zhou

et al. 2019

Aging Cell

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“…Recently, a family of epigenetic reader molecules called bromodomain and extraterminal (BET) acetyl-lysine binding proteins was shown to control pathological fibrosis 22 . JQ1, a first-inclass, potent and specific inhibitor of BET bromodomains that functions by competitively displacing BET proteins from acetylated-histones 23 , was found to block cardiac fibrosis in mice subjected to pressure overload or myocardial infarction [24][25][26] .…”

Section: Introductionmentioning

confidence: 99%

Dynamic chromatin targeting of BRD4 stimulates cardiac fibroblast activation

Stratton

Bagchi

Riching

et al. 2019

Preprint

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Small molecule inhibitors of the acetyl-histone binding protein BRD4 have been shown to block cardiac fibrosis in pre-clinical models of heart failure (HF). However, the mechanisms by which BRD4 promotes pathological myocardial fibrosis remain unclear. Here, we demonstrate that BRD4 functions as an effector of TGF-β signaling to stimulate conversion of quiescent cardiac fibroblasts into Periostin (Postn)-positive cells that express high levels of extracellular matrix.BRD4 undergoes stimulus-dependent, genome-wide redistribution in cardiac fibroblasts, becoming enriched on a subset of enhancers and super-enhancers, and leading to RNA polymerase II activation and expression of downstream target genes. Employing the SERTA domain-containing protein 4 (Sertad4) locus as a prototype, we demonstrate that dynamic chromatin targeting of BRD4 is controlled, in part, by p38 mitogen-activated protein kinase, and provide evidence of a novel function for Sertad4 in TGF-β-mediated cardiac fibroblast activation.These findings define BRD4 as a central regulator of the pro-fibrotic cell state of cardiac fibroblasts, and establish a signaling circuit for epigenetic reprogramming in HF.

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“…The BET family of proteins binds to acetylated chromatin and regulates a series of important biological events . BRD4, a heavily researched BET family member, has been demonstrated to play a key role in the progression of several types of cancer and is considered to be a compelling therapeutic target . The report verified that there was an increased expression of BRD4, indicating a pro‐oncogenic role in Cal27 cells.…”

Section: Introductionmentioning

confidence: 68%

EGFR‐mediated signaling pathway influences the sensitivity of oral squamous cell carcinoma to JQ1

Liu

Huang

et al. 2018

J of Cellular Biochemistry

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Inhibiting BRD4 has emerged as a promising anticancer strategy, and inhibitors such as JQ1 can suppress cell growth in oral squamous cell carcinoma (OSCC). However, the mechanism through which JQ1 exerts its anticancer activity has not been reported. Moreover, JQ1 does not markedly inhibit proliferation and increase apoptosis in OSCC when used as a monotherapy. Herein, we explore the mechanism of JQ1 in OSCC and probe ways to increase its therapeutic potential. In this study, we used two cell lines, Cal27, and Scc25. We found that BRD4 was highly expressed in OSCC tissues when compared with adjacent non‐tumor tissues, and JQ1 worked through the EGFR‐mediated signaling pathway in tumor cells. Furthermore, we demonstrated that JQ1 induced an increased treatment effect in vitro and in vivo when combined with a PI3K inhibitor. Interestingly, subsequent mechanistic analyses indicated that further suppressing EGFR and BRD4 expression was instrumental to this functional synergism. Moreover, we found that upregulating EGFR expression by EGF stimulation protected cells treated with JQ1 from apoptosis, while knockdown of EGFR before addition of JQ1 successfully mimicked the combination treatment results. In summary, our findings revealed that JQ1 can act by inhibiting the EGFR‐mediated signaling pathway, and EGFR expression influences the sensitivity of OSCC to JQ1. Regarding clinical use, this study demonstrates that BRD4 is a novel therapeutic target and EGFR can be used as a biomarker to identify the most appropriate anti‐BRD4 treatment strategy in OSCC.

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BRD4 inhibition for the treatment of pathological organ fibrosis

Cited by 50 publications

References 44 publications

Elevated H3K27ac in aged skeletal muscle leads to increase in extracellular matrix and fibrogenic conversion of muscle satellite cells

Elevated H3K27ac in aged skeletal muscle leads to increase in extracellular matrix and fibrogenic conversion of muscle satellite cells

Dynamic chromatin targeting of BRD4 stimulates cardiac fibroblast activation

EGFR‐mediated signaling pathway influences the sensitivity of oral squamous cell carcinoma to JQ1

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