Next Article in Journal
Gastroesophageal Reflux Disease in Idiopathic Pulmonary Fibrosis: Viewer or Actor? To Treat or Not to Treat?
Next Article in Special Issue
BET Bromodomain Degradation Disrupts Function but Not 3D Formation of RNA Pol2 Clusters
Previous Article in Journal
Design, Synthesis and Biological Investigation of 2-Anilino Triazolopyrimidines as Tubulin Polymerization Inhibitors with Anticancer Activities
Previous Article in Special Issue
Mechanistic Analysis of Chemically Diverse Bromodomain-4 Inhibitors Using Balanced QSAR Analysis and Supported by X-ray Resolved Crystal Structures
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Pharmaceuticals
Volume 15
Issue 8
10.3390/ph15081032
pharmaceuticals-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Roles of Bromodomain Extra Terminal Proteins in Metabolic Signaling and Diseases

by
Dayu Wu
1,2 and
Qiong Duan
1,2,*
1
Cardiovascular Division, The First Affiliated Hospital of Nanchang University, Nanchang 330006, China
2
Jiangxi Hypertension Research Institute, Nanchang 330006, China
*
Author to whom correspondence should be addressed.
Pharmaceuticals 2022, 15(8), 1032; https://doi.org/10.3390/ph15081032
Submission received: 11 June 2022 / Revised: 20 July 2022 / Accepted: 25 July 2022 / Published: 22 August 2022
(This article belongs to the Special Issue Bromodomains: A New Target Class for Drug Development)
Browse Figures
Review Reports Versions Notes

Abstract

:
BET proteins, which recognize and bind to acetylated histones, play a key role in transcriptional regulation. The development of chemical BET inhibitors in 2010 greatly facilitated the study of these proteins. BETs play crucial roles in cancer, inflammation, heart failure, and fibrosis. In particular, BETs may be involved in regulating metabolic processes, such as adipogenesis and metaflammation, which are under tight transcriptional regulation. In addition, acetyl-CoA links energy metabolism with epigenetic modification through lysine acetylation, which creates docking sites for BET. Given this, it is possible that the ambient energy status may dictate metabolic gene transcription via a BET-dependent mechanism. Indeed, recent studies have reported that various BET proteins are involved in both metabolic signaling regulation and disease. Here, we discuss some of the most recent information on BET proteins and their regulation of the metabolism in both cellular and animal models. Further, we summarize data from some randomized clinical trials evaluating BET inhibitors for the treatment of metabolic diseases.

1. Introduction

Epigenetic modulation involves the addition (writing) or removal (erasing) of histone modifications across the chromatin to facilitate changes in the heterochromatin allowing its transition into the open, activated euchromatin state necessary for transcription [1,2]; Lysine acetylation has emerged as an important and widespread regulatory posttranslational modification in several key proteins, including, the modification of various lysine sidechains within the unstructured amino-terminal tail of various histone proteins [1,2,3]. This process is closely associated with transcriptional regulation and is a key target in the evaluation of epigenetic diseases [3]. The bromodomain extra terminal (BET)- family of epigenetic reader proteins, including BRD2, BRD3, BRD4, and BRDT (hereafter referred to as BETs), regulate gene transcription via their recognition and binding of acetylated histones [4,5]. Given this critical role, BETs were treated as both a plausible and important therapeutic target, and investigations of these proteins facilitated the development of two sets of BET inhibitors in 2010 [6,7]. The development of these chemical BET inhibitors greatly facilitated and accelerated the study of BET family proteins, with several investigations revealing their close association with metabolic signaling [8,9,10] and diseases [11,12]. Therefore, we designed this review to evaluate the pathophysiological roles of these proteins in both normal metabolic processes and their disorders.

2. Overview of BET Bromodomain

Bromodomains, which are comprised of ~110-amino-acid modules, consist of a four-helix bundle (helices a Z, a A, a B, and a C) with a left-handed twist, and a long intervening loop between helices a Z and a A (termed the ZA loop) [13]. These bromodomain modules form a deep hydrophobic pocket that then recognizes and interacts with acetylated histone lysines, facilitating their key role in transcriptional regulation [13]. The human proteome encodes 61 BRD modules across 42 diverse proteins including several BET proteins, such as BRD2, BRD3, BRD4, and BRDT, which form a subfamily featuring two tandem bromodomains (BD1 and BD2) [3]. Both BD1 and BD2 are essential for BET activity and facilitate their interactions with acetylated chromatin [14], with each domain making a distinct functional contribution to gene transcription [15]. It was recently reported that BD1 primarily regulates steady-state gene expression, whereas the rapid increases in transcription induced by inflammatory stimuli require the activity of both the BD1 and BD2 across all of the BET proteins [15]. BRD4 is the most well-studied of these proteins and acts as the prototype for this subfamily.
The first study to report a clear connection between BETs and transcriptional regulation via their recognition of and interaction with acetylated histones was published in 2003 [14]. Further, numerous studies confirmed that BETs play a key role in transcriptional regulation. In 2005, two independent groups reported that BRD4 recruits positive transcription elongation factor b (P-TEFb) to the promoter of target genes [4,16]. P-TEFb is a heterodimer composed of cyclinT1, T2, and cyclin-dependent kinase 9 [4,16]. Upon recruitment to the promoter by BRD4, P-TEFb phosphorylates RNA polymerase II (RNAPII) inducing transcription in vivo [4,16]. In addition to recruiting P-TEFb, BET protein BRD4 also acts as an atypical kinase binding the carboxyl-terminal domain of RNAPII directly phosphorylating its serine 2 [17] and has also been shown to recognize non-histone acetylation [18]. Huang et al. reported that BRD4 binds to acetylated lysine-310 within the RelA subunit of nuclear factor (NF)-κB and enhances transcriptional activation of NF-κB and a subset of NF-κB-responsive inflammatory genes [18]. In 2013, Young et al. proposed the concept of the super enhancer, which differs from typical enhancers in size, transcription factor density and content, ability to activate transcription, and sensitivity to perturbation [19,20]. This group also identified BRD4 as a critical supporting partner for the establishment of several super enhancers known to drive the expression of various key genes associated with multiple myeloma [19]. Subsequently, other studies also reported that BRD4 is a key co-transcription factor in super enhancer-mediated gene expression across multiple biological processes [21,22]. BRD4 not only functions as a negative cotranscription factor but also a target that is positively phosphorylated or dephosphorylated by kinase or phosphatase, respectively. Wu et al. reported that casein kinase II-mediated phosphorylation of a conserved acidic region in BRD4 modulates its association with P53, modulating the expression of various P53 target genes [23]. In addition, Shu et al. found that hyper-phosphorylation of BRD4 is closely associated with resistance to BET inhibitors in triple-negative breast cancer [24]. In addition, BRD4 phosphorylation has also been shown to be involved in various cognitive activities, such as memory formation and extinction [25] (Figure 1).
These were all critical steps in establishing BET research, but these evaluations received a significant boost in 2010 when two independent groups reported structurally similar BET inhibitors in the same issue of Nature [6,7]. These studies demonstrated that BETs play a key role in controlling the expression of onco- and inflammatory genes with each of these inhibitors facilitating the functional evaluation of these BET bromodomains [6,7]. Since then, the BET bromodomain has been shown to be involved in multiple pathophysiological processes, including various cancers [26], inflammation [15,22,27], fibrosis [28], heart failure [28,29,30], and metabolic disorders [27,31]. These early BET inhibitors, including JQ1, I-BET, target both BDs equally and have similar biological effects, although they display distinct bioactivities [6,7]. RVX-208 is another important early BET inhibitor that has been shown to selectively target BD2 [32]. Recently, BD1 or BD2 selective inhibitors with better efficacy and tolerability have been developed [15]. The major BET inhibitors are listed in Table 1.

3. BET Bromodomain and Metabolic Signaling

Cells growing under sufficient energy conditions produce enough acetyl-CoA to support adenosine triphosphate (ATP) synthesis via the tricarboxylic acid (TCA) cycle and the cellular respiration, or it functions as a substrate to support histone acetylation. Given this, we can use histone lysine acetylation as a sort of “energy marker”.
Helping to inform the genome that energy is available for growth. Histone acetylation and its recognition by BET bromodomains are tightly coupled with energy metabolism. Therefore, the association between energy sensing signaling transducer and BET bromodomain are discussed initially.

3.1. Adenosine Monophosphate-Activated Protein Kinase (AMPK) and Autophagy

AMPK is a master regulator of cellular energetics. AMPK is activated in response to energy stress by sensing increases in AMP: ATP and ADP: ATP ratios. This kinase acts to restore energy balance by inhibiting anabolic processes that consume ATP, while promoting catabolic processes that generate ATP [81]. A recent study found that AMPK maintains the epigenome of mixed-lineage leukemia (MLL)-rearranged acute myeloid leukemia (AML) by linking acetyl-CoA homeostasis with BET recruitment to the chromatin. This study also showed that AMPK deletion reduces acetyl-CoA and histone acetylation, displacing BETs from the chromatin in leukemia-initiating cells, and reported that treating these cells with AMPK and BET inhibitors synergistically suppressed AML [82].
Macro autophagy/autophagy is an intracellular recycling system that delivers cytoplasmic organelles and materials to lysosomes for degradation [83]. This process is regulated by several autophagy-related (ATG) genes [84] and tightly controlled by stress-responsive signaling pathways [85]. This means, that AMPK, which acts as the primary sensor of cellular energy status, also plays a key role in promoting autophagy. In fact, a recent study has reported that BRD4 is an evolutionarily conserved autophagy repressor with BRD4 knockdown activating a series of autophagy processes including phagophore and autophagosome formation, the fusion of autophagosomes with lysosomes, and the subsequent degradation of their targets [8]. In addition, other studies have shown that nutrient deprivation disrupts the recruitment of BRD4 to the promoters of various ATG genes thus promoting autophagy. It is also worth noting that this dissociation is mediated by both AMPK and SIRT1 [8]. In summary, in the nutrient sufficient status, BRD4 suppresses autophagy that promotes growth, whereas, in the nutrient-deficient status, BRD4 facilitates cell death because the alternative source of energy, i.e., autophagy, is disrupted.

3.2. Yes-Associated Protein (YAP) and Transcriptional Coactivator with a PDZ-Binding Domain (TAZ)

YAP is a downstream Hippo reactive transcription factor, known for its critical role in cell growth [86]. TAZ is a YAP paralog from mammals regulated by the Hippo pathway and both YAP and TAZ are phosphorylated by LATS kinase and sequestered in the cytoplasm via their binding to 14-3-3 where they are ubiquitinated and degraded [86]. When LATS is inactive, dephosphorylated YAP/TAZ translocates to the nucleus to initiate transcription. YAP/TAZ do not contain their own DNA-binding motifs and initiate transcription by interacting with TEA domain family members 1–4 [87]. In addition to their classical effects on promoting cell proliferation, tissue regeneration, and oncogenesis, YAP/TAZ were recently shown to be involved in metabolic signaling. Accumulated data reveals that YAP/TAZ activity is strictly controlled by glucose homeostasis and lipid metabolism [88]. Glucose availability sustains YAP/TAZ activity by feeding the hexosamine biosynthesis pathway, while the reduction in glucose levels inhibits YAP/TAZ activity, mainly through the activation of AMPK [88]. Moreover, YAP/TAZ positively control various metabolic processes with White et al. revealing that YAP/TAZ promote glycolysis but suppress mitochondrial respiration [89]. In addition, YAP/TAZ have been shown to regulate adipogenesis [90] and thermogenesis [91], and a recent report suggests that YAP/TAZ physically engages with BRD4 guiding the genome-wide association of BRD4 [9]. In addition, treatment with small-molecule inhibitors of BRD4 blunts YAP/TAZ pro-tumorigenic activity in several cells and tissues making it an interesting mediator of transcriptional regulation [92]. YAP/TAZ are also key regulators of liver size and regeneration and Liu et al. found that the addition of a BET inhibitor suppresses YAP/TAZ-mediated transcription and liver regeneration [93]. However, whether other YAP/TAZ-regulated metabolic processes, such as thermogenesis, glycolysis, and mitochondrial respiration, are controlled by BETs remains unknown.

3.3. PGC1A

PGC-1α is a transcriptional coactivator known to control mitochondrial biogenesis and is linked to oxidative phosphorylation. PGC-1α interacts with NRF1 and 2 and stimulates mitochondrial transcription factor A, a mitochondrial matrix protein essential for the replication and transcription of mitochondrial genes. In addition, PGC-1α binds PPARα to stimulate cellular fatty acid oxidation (FAO) [94] and recent studies have shown that BRD4 coordinates with PGC-1α to control mitochondrial function and metabolism, although these outcomes and their regulation may often be in opposition under different conditions [10,95]. Padmanabhan et al. found that BRD4 interacts with GATA4 in a bromodomain-independent manner to increase the expression of PGC-1α in the heart, while BRD4 knockout suppressed PGC-1α target gene expression and mitochondrial biogenesis and function producing cardiac contractile dysfunction and lethality in various models [10]. However, in mitochondrial complex I-mutated cells, BET inhibition or BRD4 ablation actually increases oxidative phosphorylation capacity and protects against cell death [95]. This is likely mediated by the fact that BRD4 occupancy at nuclear-encoded promoters regulates the expression of mitochondrial genes and prevents PGC-1α from binding, which allows for BRD4-mediated activation of PGC-1α in normal heart tissues and PGC-1α suppression in Complex I mutated cells.

4. BET Bromodomain Functions in Fat Tissue Biology

4.1. Adipogenesis

Adipogenesis is a process where fibroblast-like progenitor cells restrict their fate to the adipogenic lineage, accumulate lipids, and differentiate into triglyceride-filled mature adipocytes. Adipocyte differentiation is controlled by the action of peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT/enhancer binding protein alpha (C/EBPα), master transcription factors known to control the gene expression program of the developing adipocyte [96]. Upon adipogenic induction, PPARγ, CEBPα, and their downstream target genes, many of which are involved in adipocyte functions such as lipid uptake and lipid synthesis, are dramatically upregulated [97]. BRD4, which is an indispensable cotranscription factor known for controlling inducible gene expression, has been shown to control proadipogenic gene expression [21]. Hu et al. reported that BETs physically associate with JMJD6 allowing for the control of its chromatin binding and proadipogenic gene transcription [98]. In addition, an analysis of BRD4 chromatin occupancy by Brown et al. revealed that the induction of adipogenesis in 3T3L1 fibroblasts provokes dynamic redistribution of BRD4 to de novo super-enhancers proximal to genes controlling adipocyte differentiation [21]. Disruption of BRD4 by siRNAs or chemical inhibitors suppresses adipogenesis, supporting a key role for BETs in adipocyte differentiation [21]. Our in vivo evaluations revealed that heterozygous BRD4 knockout in adipose tissues results in retarded body weight gain and early death (4–5 weeks) in an animal model, suggesting an indispensable role for BRD4 in fat biology [99]. This hypothesis was then further supported by the fact that treatment with JQ1 decreases both body weight and fat content [99]. In addition, Lee et al. found that BRD4 is required for the development of brown adipose tissues [100]. Although BRD2 and BRD4 belong to the BET bromodomain subfamily, it seems that they act in opposition when controlling adipogenesis. BRD2 knockdown promotes, while its overexpression suppresses, adipogenesis in 3T3L1 preadipocytes [101,102].

4.2. Lipolysis

Lipolysis is the process through which TAGs are hydrolyzed to release fatty acids (FA) for use by organs, such as the liver and skeletal muscle, when faced with carbon scarcity. Lipolysis requires at least three different enzymes: ATGL catalyzes the initial step of lipolysis, converting TGs to diacylglycerols (DGs); hormone-sensitive lipase (HSL) is primarily responsible for the hydrolysis of DGs to monoacylglycerols (MGs) and MG lipase hydrolyzes MGs [103]. These enzymes are regulated at both the transcriptional and post-transcriptional levels and while BETs are known to control inducible gene transcription, their role in controlling lipolysis gene transcription remains less defined. A recent study reported that overexpression of BRD2 promotes lipolysis in mice and 3T3L1 via ERK/HSL pathway activation and perilipin 1 degradation. In addition, myeloid lineage-specific BRD4 knockout promotes lipolysis in adipose tissue and leads to reduced obesity in mice [104]. Thus, while there is some indirect evidence supporting the inclusion of BETs in the regulation of lipolysis more studies are required to confirm and evaluate these roles.

4.3. Thermogenesis

Brown adipocytes harbor small, multilocular lipid droplets and an abundance of mitochondria, which produce heat through non-shivering thermogenesis. Heat production by BAT is governed by uncoupling protein-1 (UCP1), which resides in the inner mitochondrial membrane of brown adipocytes and functions as a long-chain fatty acid/H+ symporter to catalyze mitochondrial proton leak and thereby uncouple electron transport from ATP synthesis, with UCP1 strongly induced by cold stress [105,106]. We found that core body temperature was comparable between JQ1-treated and control mice under room temperature conditions. However, when the mice were exposed to 4 °C for 10 h, the body temperatures of the JQ1-treated mice were slightly but significantly lower than that of the control. In addition, JQ1 treatment suppressed BAT glucose uptake as determined by PET-CT scanning [99]. These data suggest that BETs may play an important role in thermogenesis, and this hypothesis was then supported by another study, which described a reduction in the thermogenic response of brown adipocytes following the addition of HDAC11. Additional evaluations revealed that this response was BRD2-dependent and an in vitro study went on to confirm that BRD2 knockdown completely blocks HDAC11 mediated suppression of Ucp1 and PGC1α mRNA, although it did not explore whether BRD2 influenced body temperature [107]. Taken together these results suggest there may be some BET-mediated regulation of thermogenesis, but more studies are needed to evaluate this role in greater detail.

4.4. Obesity

Obesity is characterized by increased fat accumulation, often resulting from excessive TAG storage in white adipose tissues following excessive TAG hydrolysis. Obesity leads to increased chronic low-grade inflammation, which impairs insulin signaling, contributing to the development of type 2 diabetes mellitus and cardiovascular diseases [108]. Hu et al. reported that deficiencies in BRD4 expression in myeloid lineage-specific cells protect mice from high-fat diet–induced obesity, inflammation, and insulin resistance in their adipose tissues [109]. In contrast to the effect of BRD4 knockout in myeloid lineage cells, genetic disruption of BRD2 (which reduces the expression of BRD2 protein) results in an extremely obese phenotype in mice with these animals reaching a weight of 60 g by 4 months of age and 90 g by 14 months, even when placed on a regular chow diet. Although disruption of BRD2 induced the development of severe obesity, knockout mice still presented with normal glycemia and glucose tolerance, and lower inflammation levels in their adipose tissues than control mice [102].

5. BET Bromodomains in Hepatic Biology

5.1. Hepatic Steatosis

Hepatic steatosis is characterized by triglyceride accumulation in hepatocytes and can progress to more severe pathologies such as nonalcoholic steatohepatitis, liver fibrosis, and cirrhosis [110]. Hepatic steatosis is an important risk factor for the development of hepatic insulin resistance and type 2 diabetes [110]. Yamada et al. reported that force-feeding fructose upregulated genes related to hepatic lipid accumulation, such as Cyp8b1, Dak, and Plin5 [111]. In addition, acetylation of histones H3 and H4, and BRD4 binding around the transcribed region of these fructose-inducible genes, were enhanced by fructose force-feeding [111]. Importantly, JQ1 treatment reduced the expression of these fructose-inducible genes, histone acetylation, and BRD4 binding around these genes [111]. Moreover, Chromatin Immunoprecipitation Sequencing (ChIP-Seq) using liver tissues from patients with non-alcoholic steatohepatitis (NASH) revealed that H3K27ac enrichment increases at gene loci associated with tumor necrosis factor α (TNFα) signaling inflammatory responses, epithelial-to mesenchymal transition, and IL2-STAT5, while BRD4 inhibition significantly reduced NASH-induced hepatocarcinogenesis [111]. Taken together, these data suggest a role for BETs in hepatic steatosis, but these relationships need further evaluation.

5.2. Hepatic Fibrosis

Fibrosis is characterized by the excessive deposition of extracellular matrix (ECM) in and around injured tissues in response to a wide variety of insults, such as inflammation, infection, and metabolic imbalance [112]. Fibrotic cells are characterized by the activation of the fibrogenic transcription programs in the myofibroblasts, which drive ECM production [28]. However, recent studies have shown that BRD4 expression is enhanced in liver fibrosis, and BETs inhibition has an anti-fibrotic effect in both the liver and other organs [112]. Ding et al. reported that BRD4 mediates a profibrotic response in activated hepatic stellate cells (HSCs), and inhibition of BRD4 blocks HSC activation into myofibroblasts, while JQ1 treatment attenuates CCl4 (carbon tetrachloride) exposure-induced hepatic fibrosis [113]. In addition, BET inhibition suppressed NASH, inflammation, and schistosomiasis-induced hepatic fibrosis [114,115,116], suggesting a broad-spectrum anti-fibrotic effect for these compounds.

5.3. HDL Biology

Plasma lipoproteins, which contain very low-density lipoprotein, low-density lipoprotein (LDL), and high-density lipoprotein (HDL), are macromolecular complexes used to transport hydrophobic lipids, cholesteryl esters, and triglycerides [117]. In addition, HDL mediates cholesterol efflux from atherosclerotic plaque via reverse cholesterol transport making it a protective lipoprotein. Apolipoprotein A-I (ApoA-I) is a critical component in HDL and is primarily produced by the liver via APOA1 gene expression. An increase in the synthesis of ApoA-I and HDL is believed to provide a new approach for treating atherosclerosis via their regulation of reverse cholesterol transport [44]. A recent study showed that administration of RVX-208, a BD2 selective BET inhibitor, for 12 weeks increased the expression of both ApoA-I and HDL-C, and promoted the production of large HDL particles, consistent with cholesterol mobilization [118]. These findings were confirmed in both a Phase 2b SUSTAIN and ASSURE clinical trials [119]. Mechanistically, BET bromodomain inhibition promotes the transcription of the APOA1 gene in human primary hepatocytes, thus improving cholesterol mobilization [44]. Thus, taken together, these studies proposed a novel therapeutic strategy for treating cardiovascular diseases, which might allow compensation for LDL-C lowering therapies widely used in the clinic.

5.4. Fatty Acid Oxidation, Gluconeogenesis, and Fasting Biology

During periods of fasting, the hepatic metabolism is programmed to initiate gluconeogenesis to maintain blood glucose levels and fatty acids oxidation to deliver fuel in the form of ketone bodies and produce hepakines to coordinate systemic energy homeostasis. These biological processes are tightly controlled at both the transcriptional and post-transcriptional levels. A recent report found that inhibition of BETs suppressed the expression of fibroblast growth factor (FGF) 15 in the ileum and decreased FGF receptor 4-related signaling in the liver, resulting in increased glucose production in the liver and hyperglycemia [31]. Mechanistically, impaired FGFR-4 signaling following BET inhibition results in increased expression of the gluconeogenesis and β-oxidation genes [31]. However, although the regulation of both gluconeogenesis and FAO gene transcription is important in carbon scarcity adaption, the influences of BETs on these genes in complex scenarios, such as extending fasting or ketogenic diet feeding, are not determined.

6. BET Bromodomains and Cardiovascular Diseases

6.1. Cardiac Metabolism and Heart Failure

Under normal conditions, the heart uses a large amount of energy when contracting but uses relatively little energy for growth. Thus, the heart primarily relies on the most energy-effective FAO for energy. However, in response to pressure overload, the heart experiences a shift away from FAO and to an increased reliance on glycolysis [120]. This change is also often coupled with transcriptional reprogramming characterized by an upregulation of the glycolytic genes and a downregulation of FAO gene expression [120]. Few studies have also revealed that BETs are likely to be involved in the transcriptional regulation of various pathological genes associated with murine transverse aortic coarctation [29]. The earliest study by Anand et al. found that BETs function as pause-release factors critical to the expression of pathological hypertrophic genes, and that inhibition of these BETs suppresses cardiomyocyte hypertrophy in vitro and pathological cardiac remodeling in vivo [30]. Subsequent studies confirmed that chemical inhibition of BETs suppressed heart failure in multiple models [28,29].
Unexpectedly, genetic deletion of BRD4 in cardiomyocytes leads to an acute deterioration in cardiac contractile function, culminating in dilated cardiomyopathy [121]. Mechanistically, BRD4 colocalizes with GATA4 at genes controlling mitochondrial bioenergy production, and BRD4 knockout results in a severe disruption of the cellular metabolism [10]. Moreover, they found that decreased BRD4 expression following heterozygous deletion results in delayed heart failure, which suggests that BRD4 may function as a critical protein scaffold in these cells via a bromodomain-independent mechanism.

6.2. BET Bromodomain in Metaflammation and Atherosclerosis

Metabolic inflammation, also known as metaflammation, is defined as low-grade, chronic inflammation orchestrated by metabolic cells in response to excess nutrients and energy [122]. Metaflammation contributes to the development of many metabolic diseases including type 2 diabetes mellitus, non-alcoholic fatty liver disease, and atherosclerosis [123]. Various papers have demonstrated that BETs are not only involved in canonical inflammation following lipopolysaccharide (LPS) exposure [27] but also control metaflammation. Our previous study showed that BETs coordinate with NF-κB to drive super enhancer production and inflammatory gene transcription [22]. Disruption of BETs by JQ1 attenuates endothelial inflammatory responses and, more importantly, atherogenic diet-induced-metaflammation and atherosclerotic lesions are significantly reduced in systems treated with JQ1 [22].
Despite this promising start, clinical trials using RVX-208 to treat atherosclerosis produced controversial outcomes. Tsujikawa et al. reported that, at least in patients with cardiovascular disorders, RVX-208 treatment reduced circulating levels of vascular inflammatory mediators, which may result in increased atherosclerotic plaque stabilization and decreased major adverse cardiac events in these patients [124]. However, another study by Nicholls et al. found that RVX-208 induced no significant increase in ApoA-I or HDL-C when compared to the placebo and that it did not induce any incremental regression in atherosclerosis [125]. Therefore, whether the application of BET inhibitors in the treatment of atherosclerosis produces any significant clinical benefit remains unclear.

7. BET Bromodomain in Diabetes

7.1. Pancreatic β Cells and Type 1 Diabetes

Pancreatic β-cells are located within the islets and produce insulin in response to enhanced glycemia and multiple neurohormonal factors. Type 1 diabetes (T1D) results from the progressive loss of pancreatic β cells as a result of autoimmune destruction [126]. BRD2 and BRD4 are highly expressed in pancreatic β-cells, where they normally inhibit β-cells mitosis and insulin transcription [102,127,128]. In fact in vitro evaluations have revealed that the specific inhibition of both BRD2 and BRD4 enhances insulin transcription, leading to increased insulin content [127]. In other studies, the evaluation of the natural history of T1D in humans and nonobese diabetic (NOD) mice reveals that these β-cells acquire a senescence-associated secretory phenotype (SASP) which is regulated by BET-mediated transcriptional control. In fact, the addition of BET inhibitor I-BET762 prevented diabetes in NOD mice and attenuated SASP in islet cells in vivo [128]. In addition, evaluations of BET bromodomain inhibitor I-BET151 significantly promoted the expansion of hPSC-derived pancreatic progenitor cells, which can be efficiently differentiated into functional pancreatic β-like cells (ePP-β cells) [129]. I-BET151 also irreversibly suppressed the development of type-1 diabetes in NOD mice by eliciting the regeneration of islet β-cells and inducing their proliferation [129]. Treatment with this compound also increases the expression of various genes encoding the necessary transcription factors for β-cell differentiation/function and induced pancreatic macrophages to adopt an anti-inflammatory phenotype.

7.2. Insulin Resistant and Type 2 Diabetes

Insulin resistance, which remains a major metabolic abnormality in the great majority of patients with Type 2 diabetes, is caused by altered functions within the insulin target cells and the accumulation of macrophages secreting proinflammatory mediators, such as IL-6, TNFα, IL-8, and MCP-1 [130]. BRD4 binds to PPARγ and increases the expression of Gdf3 in adipose tissue macrophages, resulting in increased fat accumulation and insulin resistance [109]. Myeloid lineage-specific BRD4 knockout mice fed a high-fat diet display reduced local and systemic inflammation and improved insulin sensitivity [109], while overexpression of BRD2 in white adipose tissues from wild-type mice induces insulin resistance [131]. In addition, reductions in BRD2 blocks insulin resistance even in severely obese mice [102]. These findings indicate that BRD2 and BRD4 enhance insulin resistance and are potential therapeutic targets for the clinical treatment of both insulin resistance and Type 2 diabetes.
Obesity and low-grade inflammation induce insulin resistance but a recent study showed that TNF-α inhibited insulin-stimulated glucose uptake in 3T3-L1 cells, while knockdown of BRD2 maintained their insulin sensitivity [102]. This is because BRD2 knockdown attenuates TNF-α-mediated inflammatory mRNA expression in adipocytes, indicating that BRD2 is required for TNF-α signaling and the initiation of insulin resistance in vitro [102]. Knockdown of BRD2 increased insulin-induced phosphorylation of IRS-1 and Akt, suggesting that these systems were exhibiting increased insulin sensitivity [131]. In addition, BRD2 suppresses Deptor expression, thereby activating the mTORC1 pathway, leading to feedback inhibition of insulin signaling and promoting insulin resistance [131]. The macrophage-mediated inflammatory response has also been implicated in the pathogenesis of insulin resistance. The bone marrow-derived macrophages (BMDMs) from global BRD2 reduced mice are less sensitive to LPS stimulation and have lower inflammatory cytokine production than the control BMDMs isolated from wild-type mice [27].

7.3. Clinical Evaluations of BET Inhibitors for the Treatment of Diabetes

Randomized clinical trials have recently been performed to determine the effect of BET inhibitors on diabetes. In the first trial, RVX-208 was used to treat unmedicated males with prediabetes and evaluated using an oral glucose tolerance test augmented with stable isotope tracers to facilitate postprandial plasma glucose levels, indices of insulin secretion and sensitivity, glucose kinetics, and lipolysis. These evaluations revealed that RVX-208 treatment produced a similar plasma glucose peak to the placebo, but with a more sustained elevation 30 min later. RVX-208 treatment also led to a reduction and delay in total and oral glucose secretion to the plasma and suppression of endogenous glucose production. The rate of glucose disappearance was also lower following RVX-208, with no effect on glucose oxidation or total glucose disposal [45]. These results suggest that RVX-208 delayed and reduced oral glucose absorption and endogenous glucose production, while maintaining plasma glucose levels via reduced peripheral glucose disposal. Thus, these effects may protect against the development of type 2 diabetes.
Another trial evaluated the impact of 3–6 months of RVX-208 treatment in terms of both lipid parameters and coronary atherosclerosis, and also evaluated the incidence of major adverse cardiovascular events (death, myocardial infarction, coronary revascularization, and hospitalization for cardiovascular causes). Patients treated with RVX-208 experienced fewer major adverse cardiovascular events than those treated with the placebo, and that this effect was more pronounced in patients with diabetes [132]. These results suggest that RVX-208 treated patients, particularly those with diabetes, experienced fewer cardiovascular events than the control group.
Finally, a recent phase III BETonMACE trial compared the effects of RVX-208 and placebo treatment on the incidence of major adverse cardiovascular events in 2425 patients with a recent diagnosis of the acute coronary syndrome (ACS) and diabetes. RVX-208 treated patients experienced a lower rate of the first hospitalization for heart failure, the total number of hospitalizations for heart failure, and combined cardiovascular death or hospitalization for heart failure [133]. These data indicate that RVX-208 treatment was associated with fewer hospitalizations in patients with Type 2 diabetes for heart failure and recent ACS. Taken together, these results indicate that BET inhibition may have additional clinical benefits in patients with diabetes.

8. Conclusion and Perspective

We summarized recent findings pertaining to BETs and their regulation of various metabolic processes and disorders(Figure 2), and the major conclusions are: 1. in vitro adipogenic differentiation is BET-dependent; 2. inhibition of BETs upregulates APOA1 gene expression, thereby increasing plasma HDL levels, which may improve atherosclerosis; 3. chemical inhibition of BETs and genetic deletion of BRD4 produce opposite results in the heart, suggesting BRD4 has an unknown scaffolding function; 4. randomized clinical trials of BET inhibitors in diabetes are promising.
Despite exciting progress regarding BETs and their function in the metabolism, some important issues have not been addressed. These include the fact that how BETs couple with energy metabolism for adaptive gene transcription and their involvement in the hepatic fed and fasting response remain unknown. In addition, the roles and selectivity of BD1 and BD2 in both metabolic signaling and disease progression also remain unexplored. Although there has been significant progress in this field, there are many more fundamental questions that still need to be answered. In addition, translating these findings to the clinical setting should be the focus of future studies.

Author Contributions

Writing: D.W.; conceptualization and editing: Q.D. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the National Natural Science Foundation of China (81960168).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not available.

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Acknowledgments

We are grateful to all members in Duan Laboratory. We thank Jun Qi for his valuable suggestions and comments.

Conflicts of Interest

All authors declare no financial conflict of interest.

References

  1. Ali, I.; Conrad, R.J.; Verdin, E.; Ott, M. Lysine Acetylation Goes Global: From Epigenetics to Metabolism and Therapeutics. Chem. Rev. 2018, 118, 1216–1252. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  2. Graff, J.; Tsai, L.H. Histone acetylation: Molecular mnemonics on the chromatin. Nat. Rev. Neurosci. 2013, 14, 97–111. [Google Scholar] [CrossRef] [PubMed]
  3. Fujisawa, T.; Filippakopoulos, P. Functions of bromodomain-containing proteins and their roles in homeostasis and cancer. Nat. Rev. Mol. Cell Biol. 2017, 18, 246–262. [Google Scholar] [CrossRef]
  4. Jang, M.K.; Mochizuki, K.; Zhou, M.; Jeong, H.S.; Brady, J.N.; Ozato, K. The bromodomain protein Brd4 is a positive regulatory component of P-TEFb and stimulates RNA polymerase II-dependent transcription. Mol. Cell 2005, 19, 523–534. [Google Scholar] [CrossRef] [PubMed]
  5. LeRoy, G.; Rickards, B.; Flint, S.J. The double bromodomain proteins Brd2 and Brd3 couple histone acetylation to transcription. Mol. Cell 2008, 30, 51–60. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  6. Filippakopoulos, P.; Qi, J.; Picaud, S.; Shen, Y.; Smith, W.B.; Fedorov, O.; Morse, E.M.; Keates, T.; Hickman, T.T.; Felletar, I.; et al. Selective inhibition of BET bromodomains. Nature 2010, 468, 1067–1073. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  7. Nicodeme, E.; Jeffrey, K.L.; Schaefer, U.; Beinke, S.; Dewell, S.; Chung, C.W.; Chandwani, R.; Marazzi, I.; Wilson, P.; Coste, H.; et al. Suppression of inflammation by a synthetic histone mimic. Nature 2010, 468, 1119–1123. [Google Scholar] [CrossRef] [PubMed]
  8. Sakamaki, J.I.; Wilkinson, S.; Hahn, M.; Tasdemir, N.; O’Prey, J.; Clark, W.; Hedley, A.; Nixon, C.; Long, J.S.; New, M.; et al. Bromodomain Protein BRD4 Is a Transcriptional Repressor of Autophagy and Lysosomal Function. Mol. Cell 2017, 66, 517–532.e9. [Google Scholar] [CrossRef]
  9. Zanconato, F.; Battilana, G.; Forcato, M.; Filippi, L.; Azzolin, L.; Manfrin, A.; Quaranta, E.; di Biagio, D.; Sigismondo, G.; Guzzardo, V.; et al. Transcriptional addiction in cancer cells is mediated by YAP/TAZ through BRD4. Nat. Med. 2018, 24, 1599–1610. [Google Scholar] [CrossRef] [PubMed]
  10. Padmanabhan, A.; Alexanian, M.; Linares-Saldana, R.; Gonzalez-Teran, B.; Andreoletti, G.; Huang, Y.; Connolly, A.J.; Kim, W.; Hsu, A.; Duan, Q.; et al. BRD4 (Bromodomain-Containing Protein 4) Interacts with GATA4 (GATA Binding Protein 4) to Govern Mitochondrial Homeostasis in Adult Cardiomyocytes. Circulation 2020, 142, 2338–2355. [Google Scholar] [CrossRef] [PubMed]
  11. Nicholas, D.A.; Andrieu, G.; Strissel, K.J.; Nikolajczyk, B.S.; Denis, G.V. BET bromodomain proteins and epigenetic regulation of inflammation: Implications for type 2 diabetes and breast cancer. Cell. Mol. Life Sci. 2017, 74, 231–243. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  12. Borck, P.C.; Guo, L.W.; Plutzky, J. BET Epigenetic Reader Proteins in Cardiovascular Transcriptional Programs. Circ. Res. 2020, 126, 1190–1208. [Google Scholar] [CrossRef] [PubMed]
  13. Dhalluin, C.; Carlson, J.E.; Zeng, L.; He, C.; Aggarwal, A.K.; Zhou, M.M. Structure and ligand of a histone acetyltransferase bromodomain. Nature 1999, 399, 491–496. [Google Scholar] [CrossRef]
  14. Dey, A.; Chitsaz, F.; Abbasi, A.; Misteli, T.; Ozato, K. The double bromodomain protein Brd4 binds to acetylated chromatin during interphase and mitosis. Proc. Natl. Acad. Sci. USA 2003, 100, 8758–8763. [Google Scholar] [CrossRef] [Green Version]
  15. Gilan, O.; Rioja, I.; Knezevic, K.; Bell, M.J.; Yeung, M.M.; Harker, N.R.; Lam, E.Y.N.; Chung, C.W.; Bamborough, P.; Petretich, M.; et al. Selective targeting of BD1 and BD2 of the BET proteins in cancer and immunoinflammation. Science 2020, 368, 387–394. [Google Scholar] [CrossRef] [PubMed]
  16. Yang, Z.; Yik, J.H.; Chen, R.; He, N.; Jang, M.K.; Ozato, K.; Zhou, Q. Recruitment of P-TEFb for stimulation of transcriptional elongation by the bromodomain protein Brd4. Mol. Cell 2005, 19, 535–545. [Google Scholar] [CrossRef] [PubMed]
  17. Devaiah, B.N.; Lewis, B.A.; Cherman, N.; Hewitt, M.C.; Albrecht, B.K.; Robey, P.G.; Ozato, K.; Sims, R.J., 3rd; Singer, D.S. BRD4 is an atypical kinase that phosphorylates serine2 of the RNA polymerase II carboxy-terminal domain. Proc. Natl. Acad. Sci. USA 2012, 109, 6927–6932. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  18. Huang, B.; Yang, X.D.; Zhou, M.M.; Ozato, K.; Chen, L.F. Brd4 coactivates transcriptional activation of NF-kappaB via specific binding to acetylated RelA. Mol. Cell. Biol. 2009, 29, 1375–1387. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  19. Loven, J.; Hoke, H.A.; Lin, C.Y.; Lau, A.; Orlando, D.A.; Vakoc, C.R.; Bradner, J.E.; Lee, T.I.; Young, R.A. Selective inhibition of tumor oncogenes by disruption of super-enhancers. Cell 2013, 153, 320–334. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  20. Whyte, W.A.; Orlando, D.A.; Hnisz, D.; Abraham, B.J.; Lin, C.Y.; Kagey, M.H.; Rahl, P.B.; Lee, T.I.; Young, R.A. Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell 2013, 153, 307–319. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  21. Brown, J.D.; Feldman, Z.B.; Doherty, S.P.; Reyes, J.M.; Rahl, P.B.; Lin, C.Y.; Sheng, Q.; Duan, Q.; Federation, A.J.; Kung, A.L.; et al. BET bromodomain proteins regulate enhancer function during adipogenesis. Proc. Natl. Acad. Sci. USA 2018, 115, 2144–2149. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  22. Brown, J.D.; Lin, C.Y.; Duan, Q.; Griffin, G.; Federation, A.; Paranal, R.M.; Bair, S.; Newton, G.; Lichtman, A.; Kung, A.; et al. NF-kappaB directs dynamic super enhancer formation in inflammation and atherogenesis. Mol. Cell 2014, 56, 219–231. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  23. Wu, S.Y.; Lee, A.Y.; Lai, H.T.; Zhang, H.; Chiang, C.M. Phospho switch triggers Brd4 chromatin binding and activator recruitment for gene-specific targeting. Mol. Cell 2013, 49, 843–857. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  24. Shu, S.; Lin, C.Y.; He, H.H.; Witwicki, R.M.; Tabassum, D.P.; Roberts, J.M.; Janiszewska, M.; Huh, S.J.; Liang, Y.; Ryan, J.; et al. Response and resistance to BET bromodomain inhibitors in triple-negative breast cancer. Nature 2016, 529, 413–417. [Google Scholar] [CrossRef] [Green Version]
  25. Huang, F.L.; Li, F.; Zhang, W.J.; Li, S.J.; Yang, Z.H.; Yang, T.L.; Qi, J.; Duan, Q.; Li, C.Q. Brd4 participates in epigenetic regulation of the extinction of remote auditory fear memory. Neurobiol. Learn. Mem. 2021, 179, 107383. [Google Scholar] [CrossRef] [PubMed]
  26. Belkina, A.C.; Denis, G.V. BET domain co-regulators in obesity, inflammation and cancer. Nat. Rev. Cancer 2012, 12, 465–477. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  27. Belkina, A.C.; Nikolajczyk, B.S.; Denis, G.V. BET protein function is required for inflammation: Brd2 genetic disruption and BET inhibitor JQ1 impair mouse macrophage inflammatory responses. J. Immunol. 2013, 190, 3670–3678. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  28. Duan, Q.; McMahon, S.; Anand, P.; Shah, H.; Thomas, S.; Salunga, H.T.; Huang, Y.; Zhang, R.; Sahadevan, A.; Lemieux, M.E.; et al. BET bromodomain inhibition suppresses innate inflammatory and profibrotic transcriptional networks in heart failure. Sci. Transl. Med. 2017, 9, eaah5084. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  29. Spiltoir, J.I.; Stratton, M.S.; Cavasin, M.A.; Demos-Davies, K.; Reid, B.G.; Qi, J.; Bradner, J.E.; McKinsey, T.A. BET acetyl-lysine binding proteins control pathological cardiac hypertrophy. J. Mol. Cell. Cardiol. 2013, 63, 175–179. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  30. Anand, P.; Brown, J.D.; Lin, C.Y.; Qi, J.; Zhang, R.; Artero, P.C.; Alaiti, M.A.; Bullard, J.; Alazem, K.; Margulies, K.B.; et al. BET bromodomains mediate transcriptional pause release in heart failure. Cell 2013, 154, 569–582. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  31. Kozuka, C.; Efthymiou, V.; Sales, V.M.; Zhou, L.; Osataphan, S.; Yuchi, Y.; Chimene-Weiss, J.; Mulla, C.; Isganaitis, E.; Desmond, J.; et al. Bromodomain Inhibition Reveals FGF15/19 as a Target of Epigenetic Regulation and Metabolic Control. Diabetes 2022, 71, 1023–1033. [Google Scholar] [CrossRef] [PubMed]
  32. Picaud, S.; Wells, C.; Felletar, I.; Brotherton, D.; Martin, S.; Savitsky, P.; Diez-Dacal, B.; Philpott, M.; Bountra, C.; Lingard, H.; et al. RVX-208, an inhibitor of BET transcriptional regulators with selectivity for the second bromodomain. Proc. Natl. Acad. Sci. USA 2013, 110, 19754–19759. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  33. Michaeloudes, C.; Mercado, N.; Clarke, C.; Bhavsar, P.K.; Adcock, I.M.; Barnes, P.J.; Chung, K.F. Bromodomain and extraterminal proteins suppress NF-E2-related factor 2-mediated antioxidant gene expression. J. Immunol. 2014, 192, 4913–4920. [Google Scholar] [CrossRef] [PubMed]
  34. Delmore, J.E.; Issa, G.C.; Lemieux, M.E.; Rahl, P.B.; Shi, J.; Jacobs, H.M.; Kastritis, E.; Gilpatrick, T.; Paranal, R.M.; Qi, J.; et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell 2011, 146, 904–917. [Google Scholar] [CrossRef] [Green Version]
  35. Zuber, J.; Shi, J.; Wang, E.; Rappaport, A.R.; Herrmann, H.; Sison, E.A.; Magoon, D.; Qi, J.; Blatt, K.; Wunderlich, M.; et al. RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia. Nature 2011, 478, 524–528. [Google Scholar] [CrossRef] [Green Version]
  36. Chapuy, B.; McKeown, M.R.; Lin, C.Y.; Monti, S.; Roemer, M.G.; Qi, J.; Rahl, P.B.; Sun, H.H.; Yeda, K.T.; Doench, J.G.; et al. Discovery and characterization of super-enhancer-associated dependencies in diffuse large B cell lymphoma. Cancer Cell 2013, 24, 777–790. [Google Scholar] [CrossRef] [Green Version]
  37. Abedin, S.M.; Boddy, C.S.; Munshi, H.G. BET inhibitors in the treatment of hematologic malignancies: Current insights and future prospects. OncoTargets Ther. 2016, 9, 5943–5953. [Google Scholar]
  38. Gao, Z.; Yuan, T.; Zhou, X.; Ni, P.; Sun, G.; Li, P.; Cheng, Z.; Wang, X. Targeting BRD4 proteins suppresses the growth of NSCLC through downregulation of eIF4E expression. Cancer Biol. Ther. 2018, 19, 407–415. [Google Scholar] [CrossRef]
  39. Ocana, A.; Nieto-Jimenez, C.; Pandiella, A. BET inhibitors as novel therapeutic agents in breast cancer. Oncotarget 2017, 8, 71285–71291. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  40. Zhang, Y.; Tian, S.; Xiong, J.; Zhou, Y.; Song, H.; Liu, C. JQ-1 Inhibits Colon Cancer Proliferation via Suppressing Wnt/beta-Catenin Signaling and miR-21. Chem. Res. Toxicol. 2018, 31, 302–307. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  41. Bian, B.; Juiz, N.A.; Gayet, O.; Bigonnet, M.; Brandone, N.; Roques, J.; Cros, J.; Wang, N.; Dusetti, N.; Iovanna, J. Pancreatic Cancer Organoids for Determining Sensitivity to Bromodomain and Extra-Terminal Inhibitors (BETi). Front. Oncol. 2019, 9, 475. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  42. Yu, D.; Yang, X.; Lin, J.; Cao, Z.; Lu, C.; Yang, Z.; Zheng, M.; Pan, R.; Cai, W. Super-Enhancer Induced IL-20RA Promotes Proliferation/Metastasis and Immune Evasion in Colorectal Cancer. Front. Oncol. 2021, 11, 724655. [Google Scholar] [CrossRef]
  43. Li, G.Q.; Guo, W.Z.; Zhang, Y.; Seng, J.J.; Zhang, H.P.; Ma, X.X.; Zhang, G.; Li, J.; Yan, B.; Tang, H.W.; et al. Suppression of BRD4 inhibits human hepatocellular carcinoma by repressing MYC and enhancing BIM expression. Oncotarget 2016, 7, 2462–2474. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  44. McLure, K.G.; Gesner, E.M.; Tsujikawa, L.; Kharenko, O.A.; Attwell, S.; Campeau, E.; Wasiak, S.; Stein, A.; White, A.; Fontano, E.; et al. RVX-208, an inducer of ApoA-I in humans, is a BET bromodomain antagonist. PLoS ONE 2013, 8, e83190. [Google Scholar] [CrossRef]
  45. Siebel, A.L.; Trinh, S.K.; Formosa, M.F.; Mundra, P.A.; Natoli, A.K.; Reddy-Luthmoodoo, M.; Huynh, K.; Khan, A.A.; Carey, A.L.; van Hall, G.; et al. Effects of the BET-inhibitor, RVX-208 on the HDL lipidome and glucose metabolism in individuals with prediabetes: A randomized controlled trial. Metabolism 2016, 65, 904–914. [Google Scholar] [CrossRef] [PubMed]
  46. Kulikowski, E.; Halliday, C.; Johansson, J.; Sweeney, M.; Lebioda, K.; Wong, N.; Haarhaus, M.; Brandenburg, V.; Beddhu, S.; Tonelli, M.; et al. Apabetalone Mediated Epigenetic Modulation is Associated with Favorable Kidney Function and Alkaline Phosphatase Profile in Patients with Chronic Kidney Disease. Kidney Blood Press. Res. 2018, 43, 449–457. [Google Scholar] [CrossRef] [PubMed]
  47. Cousin, S.; Blay, J.Y.; Garcia, I.B.; de Bono, J.S.; le Tourneau, C.; Moreno, V.; Trigo, J.; Hann, C.L.; Azad, A.A.; Im, S.A.; et al. Safety, pharmacokinetic, pharmacodynamic and clinical activity of molibresib for the treatment of nuclear protein in testis carcinoma and other cancers: Results of a Phase I/II open-label, dose escalation study. Int. J. Cancer 2022, 150, 993–1006. [Google Scholar] [CrossRef] [PubMed]
  48. Dawson, M.A.; Prinjha, R.K.; Dittmann, A.; Giotopoulos, G.; Bantscheff, M.; Chan, W.I.; Robson, S.C.; Chung, C.W.; Hopf, C.; Savitski, M.M.; et al. Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. Nature 2011, 478, 529–533. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  49. Kang, S.K.; Bae, H.J.; Kwon, W.S.; Kim, T.S.; Kim, K.H.; Park, S.; Yu, S.Y.; Hwang, J.; Park, J.; Chung, H.C.; et al. Inhibition of the bromodomain and extra-terminal family of epigenetic regulators as a promising therapeutic approach for gastric cancer. Cell. Oncol. 2021, 44, 1387–1403. [Google Scholar] [CrossRef] [PubMed]
  50. Alvarez-Trotta, A.; Wang, Z.; Shersher, E.; Li, B.; Long, J.; Lohse, I.; Wahlestedt, C.; El-Rifai, W.; Robbins, D.J.; Capobianco, A.J. The bromodomain inhibitor IBET-151 attenuates vismodegib-resistant esophageal adenocarcinoma growth through reduction of GLI signaling. Oncotarget 2020, 11, 3174–3187. [Google Scholar] [CrossRef] [PubMed]
  51. Gallagher, S.J.; Mijatov, B.; Gunatilake, D.; Tiffen, J.C.; Gowrishankar, K.; Jin, L.; Pupo, G.M.; Cullinane, C.; Prinjha, R.K.; Smithers, N.; et al. The epigenetic regulator I-BET151 induces BIM-dependent apoptosis and cell cycle arrest of human melanoma cells. J. Investig. Dermatol. 2014, 134, 2795–2805. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  52. Chaidos, A.; Caputo, V.; Gouvedenou, K.; Liu, B.; Marigo, I.; Chaudhry, M.S.; Rotolo, A.; Tough, D.F.; Smithers, N.N.; Bassil, A.K.; et al. Potent antimyeloma activity of the novel bromodomain inhibitors I-BET151 and I-BET762. Blood 2014, 123, 697–705. [Google Scholar] [CrossRef] [Green Version]
  53. Amorim, S.; Stathis, A.; Gleeson, M.; Iyengar, S.; Magarotto, V.; Leleu, X.; Morschhauser, F.; Karlin, L.; Broussais, F.; Rezai, K.; et al. Bromodomain inhibitor OTX015 in patients with lymphoma or multiple myeloma: A dose-escalation, open-label, pharmacokinetic, phase 1 study. Lancet Haematol. 2016, 3, e196–e204. [Google Scholar] [CrossRef]
  54. Berthon, C.; Raffoux, E.; Thomas, X.; Vey, N.; Gomez-Roca, C.; Yee, K.; Taussig, D.C.; Rezai, K.; Roumier, C.; Herait, P.; et al. Bromodomain inhibitor OTX015 in patients with acute leukaemia: A dose-escalation, phase 1 study. Lancet Haematol. 2016, 3, e186–e195. [Google Scholar] [CrossRef]
  55. Piha-Paul, S.A.; Sachdev, J.C.; Barve, M.; LoRusso, P.; Szmulewitz, R.; Patel, S.P.; Lara, P.N., Jr.; Chen, X.; Hu, B.; Freise, K.J.; et al. First-in-Human Study of Mivebresib (ABBV-075), an Oral Pan-Inhibitor of Bromodomain and Extra Terminal Proteins, in Patients with Relapsed/Refractory Solid Tumors. Clin. Cancer Res. 2019, 25, 6309–6319. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  56. Borthakur, G.; Odenike, O.; Aldoss, I.; Rizzieri, D.A.; Prebet, T.; Chen, C.; Popovic, R.; Modi, D.A.; Joshi, R.H.; Wolff, J.E.; et al. A phase 1 study of the pan-bromodomain and extraterminal inhibitor mivebresib (ABBV-075) alone or in combination with venetoclax in patients with relapsed/refractory acute myeloid leukemia. Cancer 2021, 127, 2943–2953. [Google Scholar] [CrossRef]
  57. Jiang, Y.; Wang, G.; Mu, H.; Ma, X.; Wang, Z.; Lv, Y.; Zhang, T.; Xu, J.; Wang, J.; Li, Y.; et al. Bromodomain Inhibition Attenuates the Progression and Sensitizes the Chemosensitivity of Osteosarcoma by Repressing GP130/STAT3 Signaling. Front. Oncol. 2021, 11, 642134. [Google Scholar] [CrossRef] [PubMed]
  58. Picaud, S.; da Costa, D.; Thanasopoulou, A.; Filippakopoulos, P.; Fish, P.V.; Philpott, M.; Fedorov, O.; Brennan, P.; Bunnage, M.E.; Owen, D.R.; et al. PFI-1, a highly selective protein interaction inhibitor, targeting BET Bromodomains. Cancer Res. 2013, 73, 3336–3346. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  59. Faivre, E.J.; McDaniel, K.F.; Albert, D.H.; Mantena, S.R.; Plotnik, J.P.; Wilcox, D.; Zhang, L.; Bui, M.H.; Sheppard, G.S.; Wang, L.; et al. Selective inhibition of the BD2 bromodomain of BET proteins in prostate cancer. Nature 2020, 578, 306–310. [Google Scholar] [CrossRef]
  60. Roboz, G.J.; Desai, P.; Lee, S.; Ritchie, E.K.; Winer, E.S.; DeMario, M.; Brennan, B.; Nuesch, E.; Chesne, E.; Brennan, L.; et al. A dose escalation study of RO6870810/TEN-10 in patients with acute myeloid leukemia and myelodysplastic syndrome. Leuk. Lymphoma 2021, 62, 1740–1748. [Google Scholar] [CrossRef] [PubMed]
  61. Shapiro, G.I.; LoRusso, P.; Dowlati, A.; TDo, K.; Jacobson, C.A.; Vaishampayan, U.; Weise, A.; Caimi, P.F.; Eder, J.P.; French, C.A.; et al. A Phase 1 study of RO6870810, a novel bromodomain and extra-terminal protein inhibitor, in patients with NUT carcinoma, other solid tumours, or diffuse large B-cell lymphoma. Br. J. Cancer 2021, 124, 744–753. [Google Scholar] [CrossRef]
  62. Ramasamy, K.; Nooka, A.; Quach, H.; Htut, M.; Popat, R.; Liedtke, M.; Tuchman, S.A.; Laubach, J.; Gasparetto, C.; Chanan-Khan, A.; et al. A phase 1b dose-escalation/expansion study of BET inhibitor RO6870810 in patients with advanced multiple myeloma. Blood Cancer J. 2021, 11, 149. [Google Scholar] [CrossRef]
  63. Postel-Vinay, S.; Herbschleb, K.; Massard, C.; Woodcock, V.; Soria, J.C.; Walter, A.O.; Ewerton, F.; Poelman, M.; Benson, N.; Ocker, M.; et al. First-in-human phase I study of the bromodomain and extraterminal motif inhibitor BAY 1238097: Emerging pharmacokinetic/pharmacodynamic relationship and early termination due to unexpected toxicity. Eur. J. Cancer 2019, 109, 103–110. [Google Scholar] [CrossRef] [PubMed]
  64. Jauset, T.; Masso-Valles, D.; Martinez-Martin, S.; Beaulieu, M.E.; Foradada, L.; Fiorentino, F.P.; Yokota, J.; Haendler, B.; Siegel, S.; Whitfield, J.R.; et al. BET inhibition is an effective approach against KRAS-driven PDAC and NSCLC. Oncotarget 2018, 9, 18734–18746. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  65. Bernasconi, E.; Gaudio, E.; Lejeune, P.; Tarantelli, C.; Cascione, L.; Kwee, I.; Spriano, F.; Rinaldi, A.; Mensah, A.A.; Chung, E.; et al. Preclinical evaluation of the BET bromodomain inhibitor BAY 1238097 for the treatment of lymphoma. Br. J. Haematol. 2017, 178, 936–948. [Google Scholar] [PubMed] [Green Version]
  66. Aggarwal, R.R.; Schweizer, M.T.; Nanus, D.M.; Pantuck, A.J.; Heath, E.I.; Campeau, E.; Attwell, S.; Norek, K.; Snyder, M.; Bauman, L.; et al. A Phase Ib/IIa Study of the Pan-BET Inhibitor ZEN-3694 in Combination with Enzalutamide in Patients with Metastatic Castration-resistant Prostate Cancer. Clin. Cancer Res. 2020, 26, 5338–5347. [Google Scholar] [CrossRef]
  67. Falchook, G.; Rosen, S.; LoRusso, P.; Watts, J.; Gupta, S.; Coombs, C.C.; Talpaz, M.; Kurzrock, R.; Mita, M.; Cassaday, R.; et al. Development of 2 Bromodomain and Extraterminal Inhibitors with Distinct Pharmacokinetic and Pharmacodynamic Profiles for the Treatment of Advanced Malignancies. Clin. Cancer Res. 2020, 26, 1247–1257. [Google Scholar] [CrossRef] [Green Version]
  68. Ameratunga, M.; Brana, I.; Bono, P.; Postel-Vinay, S.; Plummer, R.; Aspegren, J.; Korjamo, T.; Snapir, A.; de Bono, J.S. First-in-human Phase 1 open label study of the BET inhibitor ODM-207 in patients with selected solid tumours. Br. J. Cancer 2020, 123, 1730–1736. [Google Scholar] [CrossRef] [PubMed]
  69. Moreno, V.; Sepulveda, J.M.; Vieito, M.; Hernandez-Guerrero, T.; Doger, B.; Saavedra, O.; Ferrero, O.; Sarmiento, R.; Arias, M.; de Alvaro, J.; et al. Phase I study of CC-90010, a reversible, oral BET inhibitor in patients with advanced solid tumors and relapsed/refractory non-Hodgkin’s lymphoma. Ann. Oncol. 2020, 31, 780–788. [Google Scholar] [CrossRef] [PubMed]
  70. Lu, J.; Qian, Y.; Altieri, M.; Dong, H.; Wang, J.; Raina, K.; Hines, J.; Winkler, J.D.; Crew, A.P.; Coleman, K.; et al. Hijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target BRD4. Chem. Biol. 2015, 22, 755–763. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  71. Zhang, X.; Lee, H.C.; Shirazi, F.; Baladandayuthapani, V.; Lin, H.; Kuiatse, I.; Wang, H.; Jones, R.J.; Berkova, Z.; Singh, R.K.; et al. Protein targeting chimeric molecules specific for bromodomain and extra-terminal motif family proteins are active against pre-clinical models of multiple myeloma. Leukemia 2018, 32, 2224–2239. [Google Scholar] [CrossRef] [PubMed]
  72. Saenz, D.T.; Fiskus, W.; Qian, Y.; Manshouri, T.; Rajapakshe, K.; Raina, K.; Coleman, K.G.; Crew, A.P.; Shen, A.; Mill, C.P.; et al. Novel BET protein proteolysis-targeting chimera exerts superior lethal activity than bromodomain inhibitor (BETi) against post-myeloproliferative neoplasm secondary (s) AML cells. Leukemia 2017, 31, 1951–1961. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  73. Winter, G.E.; Buckley, D.L.; Paulk, J.; Roberts, J.M.; Souza, A.; Dhe-Paganon, S.; Bradner, J.E. Phthalimide conjugation as a strategy for in vivo target protein degradation. Science 2015, 348, 1376–1381. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  74. Raina, K.; Lu, J.; Qian, Y.; Altieri, M.; Gordon, D.; Rossi, A.M.; Wang, J.; Chen, X.; Dong, H.; Siu, K.; et al. PROTAC-induced BET protein degradation as a therapy for castration-resistant prostate cancer. Proc. Natl. Acad. Sci. USA 2016, 113, 7124–7129. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  75. Deng, Y.; Yu, C.; Chen, L.; Zhang, X.; Lei, Q.; Liu, Q.; Cai, G.; Liu, F. ARV-771 Acts as an Inducer of Cell Cycle Arrest and Apoptosis to Suppress Hepatocellular Carcinoma Progression. Front. Pharmacol. 2022, 13, 858901. [Google Scholar] [CrossRef] [PubMed]
  76. Wang, J.; Xu, Y.; Rao, X.; Zhang, R.; Tang, J.; Zhang, D.; Jie, X.; Zhu, K.; Wang, X.; Xu, Y.; et al. BRD4-IRF1 axis regulates chemoradiotherapy-induced PD-L1 expression and immune evasion in non-small cell lung cancer. Clin. Transl. Med. 2022, 12, e718. [Google Scholar] [CrossRef] [PubMed]
  77. Saenz, D.T.; Fiskus, W.; Manshouri, T.; Mill, C.P.; Qian, Y.; Raina, K.; Rajapakshe, K.; Coarfa, C.; Soldi, R.; Bose, P.; et al. Targeting nuclear beta-catenin as therapy for post-myeloproliferative neoplasm secondary AML. Leukemia 2019, 33, 1373–1386. [Google Scholar] [CrossRef] [PubMed]
  78. Qin, C.; Hu, Y.; Zhou, B.; Fernandez-Salas, E.; Yang, C.Y.; Liu, L.; McEachern, D.; Przybranowski, S.; Wang, M.; Stuckey, J.; et al. Discovery of QCA570 as an Exceptionally Potent and Efficacious Proteolysis Targeting Chimera (PROTAC) Degrader of the Bromodomain and Extra-Terminal (BET) Proteins Capable of Inducing Complete and Durable Tumor Regression. J. Med. Chem. 2018, 61, 6685–6704. [Google Scholar] [CrossRef] [PubMed]
  79. Bai, L.; Zhou, B.; Yang, C.Y.; Ji, J.; McEachern, D.; Przybranowski, S.; Jiang, H.; Hu, J.; Xu, F.; Zhao, Y.; et al. Targeted Degradation of BET Proteins in Triple-Negative Breast Cancer. Cancer Res. 2017, 77, 2476–2487. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  80. Shafran, J.S.; Jafari, N.; Casey, A.N.; Gyorffy, B.; Denis, G.V. BRD4 regulates key transcription factors that drive epithelial-mesenchymal transition in castration-resistant prostate cancer. Prostate Cancer Prostatic Dis. 2021, 24, 268–277. [Google Scholar] [CrossRef] [PubMed]
  81. Garcia, D.; Shaw, R.J. AMPK: Mechanisms of Cellular Energy Sensing and Restoration of Metabolic Balance. Mol. Cell 2017, 66, 789–800. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  82. Jiang, Y.; Hu, T.; Wang, T.; Shi, X.; Kitano, A.; Eagle, K.; Hoegenauer, K.A.; Konopleva, M.Y.; Lin, C.Y.; Young, N.L.; et al. AMP-activated protein kinase links acetyl-CoA homeostasis to BRD4 recruitment in acute myeloid leukemia. Blood 2019, 134, 2183–2194. [Google Scholar] [CrossRef]
  83. Mizushima, N.; Levine, B.; Cuervo, A.M.; Klionsky, D.J. Autophagy fights disease through cellular self-digestion. Nature 2008, 451, 1069–1075. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  84. Xie, Z.; Klionsky, D.J. Autophagosome formation: Core machinery and adaptations. Nat. Cell Biol. 2007, 9, 1102–1109. [Google Scholar] [CrossRef]
  85. Kuma, A.; Hatano, M.; Matsui, M.; Yamamoto, A.; Nakaya, H.; Yoshimori, T.; Ohsumi, Y.; Tokuhisa, T.; Mizushima, N. The role of autophagy during the early neonatal starvation period. Nature 2004, 432, 1032–1036. [Google Scholar] [CrossRef] [PubMed]
  86. Dong, J.; Feldmann, G.; Huang, J.; Wu, S.; Zhang, N.; Comerford, S.A.; Gayyed, M.F.; Anders, R.A.; Maitra, A.; Pan, D. Elucidation of a universal size-control mechanism in Drosophila and mammals. Cell 2007, 130, 1120–1133. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  87. Zhao, B.; Ye, X.; Yu, J.; Li, L.; Li, W.; Li, S.; Yu, J.; Lin, J.D.; Wang, C.Y.; Chinnaiyan, A.M.; et al. TEAD mediates YAP-dependent gene induction and growth control. Genes Dev. 2008, 22, 1962–1971. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  88. Koo, J.H.; Guan, K.L. Interplay between YAP/TAZ and Metabolism. Cell Metab. 2018, 28, 196–206. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  89. White, S.M.; Avantaggiati, M.L.; Nemazanyy, I.; di Poto, C.; Yang, Y.; Pende, M.; Gibney, G.T.; Ressom, H.W.; Field, J.; Atkins, M.B.; et al. YAP/TAZ Inhibition Induces Metabolic and Signaling Rewiring Resulting in Targetable Vulnerabilities in NF2-Deficient Tumor Cells. Dev. Cell 2019, 49, 425–443.e9. [Google Scholar] [CrossRef]
  90. Yu, F.X.; Zhang, Y.; Park, H.W.; Jewell, J.L.; Chen, Q.; Deng, Y.; Pan, D.; Taylor, S.S.; Lai, Z.C.; Guan, K.L. Protein kinase A activates the Hippo pathway to modulate cell proliferation and differentiation. Genes Dev. 2013, 27, 1223–1232. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  91. Tharp, K.M.; Kang, M.S.; Timblin, G.A.; Dempersmier, J.; Dempsey, G.E.; Zushin, P.H.; Benavides, J.; Choi, C.; Li, C.X.; Jha, A.K.; et al. Actomyosin-Mediated Tension Orchestrates Uncoupled Respiration in Adipose Tissues. Cell Metab. 2018, 27, 602–615.e4. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  92. Nguyen, C.D.K.; Yi, C. YAP/TAZ Signaling and Resistance to Cancer Therapy. Trends Cancer 2019, 5, 283–296. [Google Scholar] [CrossRef] [PubMed]
  93. Liu, C.; Cheng, X.; Chen, J.; Wang, Y.; Wu, X.; Tian, R.; Liu, B.; Ding, X.; Sun, Q.; Gong, W. Suppression of YAP/TAZ-Notch1-NICD axis by bromodomain and extraterminal protein inhibition impairs liver regeneration. Theranostics 2019, 9, 3840–3852. [Google Scholar] [CrossRef]
  94. Lin, J.; Handschin, C.; Spiegelman, B.M. Metabolic control through the PGC-1 family of transcription coactivators. Cell Metab. 2005, 1, 361–370. [Google Scholar] [CrossRef] [Green Version]
  95. Barrow, J.J.; Balsa, E.; Verdeguer, F.; Tavares, C.D.; Soustek, M.S.; Hollingsworth, L.R.T.; Jedrychowski, M.; Vogel, R.; Paulo, J.A.; Smeitink, J.; et al. Bromodomain Inhibitors Correct Bioenergetic Deficiency Caused by Mitochondrial Disease Complex I Mutations. Mol. Cell 2016, 64, 163–175. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  96. Tontonoz, P.; Hu, E.; Spiegelman, B.M. Stimulation of adipogenesis in fibroblasts by PPAR gamma 2, a lipid-activated transcription factor. Cell 1994, 79, 1147–1156. [Google Scholar] [CrossRef]
  97. Sarjeant, K.; Stephens, J.M. Adipogenesis. Cold Spring Harb. Perspect. Biol. 2012, 4, a008417. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  98. Hu, Y.J.; Belaghzal, H.; Hsiao, W.Y.; Qi, J.; Bradner, J.E.; Guertin, D.A.; Sif, S.; Imbalzano, A.N. Transcriptional and post-transcriptional control of adipocyte differentiation by Jumonji domain-containing protein 6. Nucleic Acids Res. 2015, 43, 7790–7804. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  99. Duan, Q.; Wu, P.; Liu, Z.; Xia, F.; Zhu, L.; Zheng, Z.; Yang, T.; Qi, J. BET bromodomain inhibition suppresses adipogenesis in mice. Endocrine 2020, 67, 264–267. [Google Scholar] [CrossRef] [PubMed]
  100. Lee, J.E.; Park, Y.K.; Park, S.; Jang, Y.; Waring, N.; Dey, A.; Ozato, K.; Lai, B.; Peng, W.; Ge, K. Brd4 binds to active enhancers to control cell identity gene induction in adipogenesis and myogenesis. Nat. Commun. 2017, 8, 2217. [Google Scholar] [CrossRef] [PubMed]
  101. Zang, K.; Wang, J.; Dong, M.; Sun, R.; Wang, Y.; Huang, Y.; Liu, X.; Li, Y.; Wang, F.; Yu, M. Brd2 inhibits adipogenesis via the ERK1/2 signaling pathway in 3T3-L1 adipocytes. PLoS ONE 2013, 8, e78536. [Google Scholar] [CrossRef] [Green Version]
  102. Wang, F.; Liu, H.; Blanton, W.P.; Belkina, A.; Lebrasseur, N.K.; Denis, G.V. Brd2 disruption in mice causes severe obesity without Type 2 diabetes. Biochem. J. 2009, 425, 71–83. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  103. Zechner, R.; Zimmermann, R.; Eichmann, T.O.; Kohlwein, S.D.; Haemmerle, G.; Lass, A.; Madeo, F. FAT SIGNALS–lipases and lipolysis in lipid metabolism and signaling. Cell Metab. 2012, 15, 279–291. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  104. Zong, J.; Li, S.; Wang, Y.; Mo, W.; Sun, R.; Yu, M. Bromodomain-containing protein 2 promotes lipolysis via ERK/HSL signalling pathway in white adipose tissue of mice. Gen. Comp. Endocrinol. 2019, 281, 105–116. [Google Scholar] [CrossRef]
  105. Fedorenko, A.; Lishko, P.V.; Kirichok, Y. Mechanism of fatty-acid-dependent UCP1 uncoupling in brown fat mitochondria. Cell 2012, 151, 400–413. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  106. Nicholls, D.G.; Bernson, V.S.; Heaton, G.M. The identification of the component in the inner membrane of brown adipose tissue mitochondria responsible for regulating energy dissipation. Eff. Thermogenesis 1978, 32, 89–93. [Google Scholar]
  107. Bagchi, R.A.; Ferguson, B.S.; Stratton, M.S.; Hu, T.; Cavasin, M.A.; Sun, L.; Lin, Y.H.; Liu, D.; Londono, P.; Song, K.; et al. HDAC11 suppresses the thermogenic program of adipose tissue via BRD2. JCI Insight 2018, 3, e120159. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  108. Ghaben, A.L.; Scherer, P.E. Adipogenesis and metabolic health. Nat. Rev. Mol. Cell Biol. 2019, 20, 242–258. [Google Scholar] [CrossRef]
  109. Hu, X.; Dong, X.; Li, G.; Chen, Y.; Chen, J.; He, X.; Sun, H.; Kim, D.H.; Kemper, J.K.; Chen, L.F. Brd4 modulates diet-induced obesity via PPARgamma-dependent Gdf3 expression in adipose tissue macrophages. JCI Insight 2021, 6, e143379. [Google Scholar] [CrossRef]
  110. Baiceanu, A.; Mesdom, P.; Lagouge, M.; Foufelle, F. Endoplasmic reticulum proteostasis in hepatic steatosis. Nat. Rev. Endocrinol. 2016, 12, 710–722. [Google Scholar] [CrossRef]
  111. Yamada, A.; Honma, K.; Mochizuki, K.; Goda, T. BRD4 regulates fructose-inducible lipid accumulation-related genes in the mouse liver. Metabolism 2016, 65, 1478–1488. [Google Scholar] [CrossRef] [PubMed]
  112. Wu, C.; Cheng, D.; Peng, Y.; Li, Y.; Fu, C.; Wang, Y.; Fu, L.; Peng, S.; Ni, X. Hepatic BRD4 Is Upregulated in Liver Fibrosis of Various Etiologies and Positively Correlated to Fibrotic Severity. Front. Med. 2021, 8, 683506. [Google Scholar] [CrossRef] [PubMed]
  113. Ding, N.; Hah, N.; Yu, R.T.; Sherman, M.H.; Benner, C.; Leblanc, M.; He, M.; Liddle, C.; Downes, M.; Evans, R.M. BRD4 is a novel therapeutic target for liver fibrosis. Proc. Natl. Acad. Sci. USA 2015, 112, 15713–15718. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  114. Gao, J.; Wei, B.; Liu, M.; Hirsova, P.; Sehrawat, T.S.; Cao, S.; Hu, X.; Xue, F.; Yaqoob, U.; Kang, N.; et al. Endothelial p300 Promotes Portal Hypertension and Hepatic Fibrosis Through C-C Motif Chemokine Ligand 2-Mediated Angiocrine Signaling. Hepatology 2021, 73, 2468–2483. [Google Scholar] [CrossRef] [PubMed]
  115. Ding, H.; Yang, X.; Tian, J.; Wang, X.; Ji, Y.; El-Ashram, S.; Ren, C.; Shen, J.; Liu, M. JQ-1 ameliorates schistosomiasis liver fibrosis by suppressing JAK2 and STAT3 activation. Biomed. Pharmacother. 2021, 144, 112281. [Google Scholar] [CrossRef] [PubMed]
  116. Fu, R.; Zu, S.J.; Liu, Y.J.; Li, J.C.; Dang, W.Z.; Liao, L.P.; Liu, L.P.; Chen, P.Y.; Huang, H.M.; Wu, K.H.; et al. Selective bromodomain and extra-terminal bromodomain inhibitor inactivates macrophages and hepatic stellate cells to inhibit liver inflammation and fibrosis. Bioengineered 2022, 13, 10914–10930. [Google Scholar] [CrossRef]
  117. Dixon, J.L.; Ginsberg, H.N. Hepatic synthesis of lipoproteins and apolipoproteins. Semin. Liver Dis. 1992, 12, 364–372. [Google Scholar] [CrossRef]
  118. Nicholls, S.J.; Gordon, A.; Johansson, J.; Wolski, K.; Ballantyne, C.M.; Kastelein, J.J.; Taylor, A.; Borgman, M.; Nissen, S.E. Efficacy and safety of a novel oral inducer of apolipoprotein a-I synthesis in statin-treated patients with stable coronary artery disease a randomized controlled trial. J. Am. Coll. Cardiol. 2011, 57, 1111–1119. [Google Scholar] [CrossRef] [Green Version]
  119. Gilham, D.; Wasiak, S.; Tsujikawa, L.M.; Halliday, C.; Norek, K.; Patel, R.G.; Kulikowski, E.; Johansson, J.; Sweeney, M.; Wong, N.C.; et al. RVX-208, a BET-inhibitor for treating atherosclerotic cardiovascular disease, raises ApoA-I/HDL and represses pathways that contribute to cardiovascular disease. Atherosclerosis 2016, 247, 48–57. [Google Scholar] [CrossRef] [Green Version]
  120. Allard, M.F.; Schonekess, B.O.; Henning, S.L.; English, D.R.; Lopaschuk, G.D. Contribution of oxidative metabolism and glycolysis to ATP production in hypertrophied hearts. Am. J. Physiol. 1994, 267 Pt 2, H742–H750. [Google Scholar] [CrossRef]
  121. Kim, S.Y.; Zhang, X.; Schiattarella, G.G.; Altamirano, F.; Ramos, T.A.R.; French, K.M.; Jiang, N.; Szweda, P.A.; Evers, B.M.; May, H.I.; et al. Epigenetic Reader BRD4 (Bromodomain-Containing Protein 4) Governs Nucleus-Encoded Mitochondrial Transcriptome to Regulate Cardiac Function. Circulation 2020, 142, 2356–2370. [Google Scholar] [CrossRef]
  122. Hotamisligil, G.S. Inflammation and metabolic disorders. Nature 2006, 444, 860–867. [Google Scholar] [CrossRef]
  123. Christ, A.; Lauterbach, M.; Latz, E. Western Diet and the Immune System: An Inflammatory Connection. Immunity 2019, 51, 794–811. [Google Scholar] [CrossRef] [PubMed]
  124. Tsujikawa, L.M.; Fu, L.; Das, S.; Halliday, C.; Rakai, B.D.; Stotz, S.C.; Sarsons, C.D.; Gilham, D.; Daze, E.; Wasiak, S.; et al. Apabetalone (RVX-208) reduces vascular inflammation in vitro and in CVD patients by a BET-dependent epigenetic mechanism. Clin. Epigenetics 2019, 11, 102. [Google Scholar] [CrossRef] [PubMed]
  125. Nicholls, S.J.; Puri, R.; Wolski, K.; Ballantyne, C.M.; Barter, P.J.; Brewer, H.B.; Kastelein, J.J.; Hu, B.; Uno, K.; Kataoka, Y.; et al. Effect of the BET Protein Inhibitor, RVX-208, on Progression of Coronary Atherosclerosis: Results of the Phase 2b, Randomized, Double-Blind, Multicenter, ASSURE Trial. Am. J. Cardiovasc. Drugs 2016, 16, 55–65. [Google Scholar] [CrossRef]
  126. Bluestone, J.A.; Herold, K.; Eisenbarth, G. Genetics, pathogenesis and clinical interventions in type 1 diabetes. Nature 2010, 464, 1293–1300. [Google Scholar] [CrossRef] [Green Version]
  127. Deeney, J.T.; Belkina, A.C.; Shirihai, O.S.; Corkey, B.E.; Denis, G.V. BET Bromodomain Proteins Brd2, Brd3 and Brd4 Selectively Regulate Metabolic Pathways in the Pancreatic beta-Cell. PLoS ONE 2016, 11, e0151329. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  128. Thompson, P.J.; Shah, A.; Apostolopolou, H.; Bhushan, A. BET Proteins Are Required for Transcriptional Activation of the Senescent Islet Cell Secretome in Type 1 Diabetes. Int. J. Mol. Sci. 2019, 20, 4776. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  129. Ma, X.; Lu, Y.; Zhou, Z.; Li, Q.; Chen, X.; Wang, W.; Jin, Y.; Hu, Z.; Chen, G.; Deng, Q.; et al. Human expandable pancreatic progenitor-derived beta cells ameliorate diabetes. Sci. Adv. 2022, 8, eabk1826. [Google Scholar] [CrossRef] [PubMed]
  130. Olefsky, J.M.; Glass, C.K. Macrophages, inflammation, and insulin resistance. Annu. Rev. Physiol. 2010, 72, 219–246. [Google Scholar] [CrossRef] [PubMed]
  131. Sun, R.; Wu, Y.; Hou, W.; Sun, Z.; Wang, Y.; Wei, H.; Mo, W.; Yu, M. Bromodomain-containing protein 2 induces insulin resistance via the mTOR/Akt signaling pathway and an inflammatory response in adipose tissue. Cell. Signal. 2017, 30, 92–103. [Google Scholar] [CrossRef] [PubMed]
  132. Nicholls, S.J.; Ray, K.K.; Johansson, J.O.; Gordon, A.; Sweeney, M.; Halliday, C.; Kulikowski, E.; Wong, N.; Kim, S.W.; Schwartz, G.G. Selective BET Protein Inhibition with Apabetalone and Cardiovascular Events: A Pooled Analysis of Trials in Patients with Coronary Artery Disease. Am. J. Cardiovasc. Drugs 2018, 18, 109–115. [Google Scholar] [CrossRef] [PubMed]
  133. Nicholls, S.J.; Schwartz, G.G.; Buhr, K.A.; Ginsberg, H.N.; Johansson, J.O.; Kalantar-Zadeh, K.; Kulikowski, E.; Toth, P.P.; Wong, N.; Sweeney, M.; et al. Apabetalone and hospitalization for heart failure in patients following an acute coronary syndrome: A prespecified analysis of the BETonMACE study. Cardiovasc. Diabetol. 2021, 20, 13. [Google Scholar] [CrossRef] [PubMed]
Pharmaceuticals 15 01032 g001 550
Figure 1. The development process of BET bromodomain proteins. P-TEFb: Positive Transcription Elongation Factor b. SEs: Super Enhancers.
Figure 1. The development process of BET bromodomain proteins. P-TEFb: Positive Transcription Elongation Factor b. SEs: Super Enhancers.
Pharmaceuticals 15 01032 g001
Pharmaceuticals 15 01032 g002 550
Figure 2. Role of BETs in metabolic processes and disorders. IR, insulin resistance; AS, atherosclerosis; T2DM, type 2 diabetes mellitus; NAFLD, nonalcoholic fatty liver disease; SASP, senescence-associated secretory phenotype; T1D, type 1 diabetes.
Figure 2. Role of BETs in metabolic processes and disorders. IR, insulin resistance; AS, atherosclerosis; T2DM, type 2 diabetes mellitus; NAFLD, nonalcoholic fatty liver disease; SASP, senescence-associated secretory phenotype; T1D, type 1 diabetes.
Pharmaceuticals 15 01032 g002
Table
Table 1. Summary of Drugs Targeting BET Proteins.
Table 1. Summary of Drugs Targeting BET Proteins.
CompoundSelectivityIndicationReference
BET inhibitorsJQ1BD1 and BD2 from BRD2/3/4 and BRDTChronic obstructive pulmonary disease[33]
NUT midline carcinoma [6]
Multiple myeloma[34]
Acute myeloid leukemia[35]
Diffuse large B-cell lymphoma [36]
Hematologic malignancies[37]
Lung cancer[38]
Breast cancer[39]
Colon cancer[40]
Pancreatic ductal adenocarcinoma[41]
Colorectal cancer[42]
Hepatocellular cancer[43]
RVX-208BD2 from BRD2,3,4Atherosclerosis[44]
Diabetes[45]
Fabry disease[12]
Chronic kidney disease[46]
IBET-762
(GSK-525762)		BD1 and BD2 from
BRD2,3,4,T		Neoplasm[12]
Testis carcinoma[47]
Midline carcinoma[12]
IBET-151
BD1 and BD2 from
BRD2,3,4,T		MLL-fusion leukemia[48]
Colorectal ctumorsancer[42]
Gastric cancer[49]
Vismodegib-resistant esophageal adenocarcinoma[50]
Rheumatoid arthritis[15]
Melanoma[51]
Myeloma[52]
MK8628/OTXO15BRD2,3,4Lymphoma or multiple myeloma[53]
Acute leukemia[54]
NUT midline carcinoma[12]
Triple-negative breast cancer
Lung cancer
Castration-resistantprostate cancer
FT1101BRD2,3,4,TAcute myeloid leukemia[12]
Non-Hodgkin lymphoma
CPI-0610BD1 from
BRD2,4,T		Multiple myeloma[12]
ABBV-075
Mivebresib
BRD2,3,4Relapsed/Refractory solid tumors.[55]
Breast cancer[12]
Prostate cancer
Non-Hodgkin lymphoma
Multiple myeloma
Relapsed/refractory acute myeloid leukemia.[56]
NHWD-870BRD4Pancreatic ductal adenocarcinoma [41]
Osteosarcoma[57]
BMS-986158undisclosedAdvanced tumors[12]
PFI-1BRD2,4Acute leukemia[58]
ABBV-744BD2prostate cancer[59]
Acute myeloid leukemia[59]
GSK788BD1Acute myeloid leukemia [15]
GSK620BD2Rheumatoid arthritis[15]
Psoriasis[15]
Non–alcoholic fatty liver disease [15]
RO6870810/TEN-10undisclosedAcute myeloid leukemia
and myelodysplastic syndrome		[60]
NUT carcinoma, other solid tumors, or diffuse large B-cell lymphoma[61]
Multiple myeloma[62]
BAY 1238097
BRD4Advanced malignancies[63]
Pancreatic ductal adenocarcinoma
Non-small cell lung cancer 		[64]
Lymphoma[65]
ZEN-3694BD1,BD2Metastatic castration-resistant prostate cancer[66]
INCB054329BRD4Advanced malignancies[67]
INCB057643BRD4Advanced malignancies[67]
ODM-207BRD2,3,4,TCastration-resistantprostate cancer.[68]
AZD5153BRD4Malignant solid tumor and lymphomaNCT03205176
CC-90010BRD2,4Advanced solid tumors and relapsed/refractory Non-Hodgkin’s lymphoma.[69]
Solid tumor[69]
BET degradersARV-825BRD2,3,4,TBurkitt’s lymphoma [70]
Multiple myeloma[71]
Secondary (s) acute myeloid leukemia[72]
dBET1BRD2,3,4Leukemia[73]
ARV-763BRD4Multiple myeloma[71]
ARV-771BRD2,3,4Castration-resistant prostate cancer[74]
Hepatocellular carcinoma [75]
Non-small cell lung cancer[76]
Post-myeloproliferative neoplasm secondary acute myeloid leukemia [77]
QCA570BRD4Acute leukemia[78]
BETd-246/BETd-260BRD4Triple-negative breast cancer
[79]
MZ1BRD4Castration-resistant prostate cancer
[80]
The compounds are listed according to their (1) mechanism of action in blocking BETs function; (2) selectivity for BET family proteins; (3) condition or diseases for which they are being studied. BET indicates bromodomain extra terminal.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Wu, D.; Duan, Q. Roles of Bromodomain Extra Terminal Proteins in Metabolic Signaling and Diseases. Pharmaceuticals 2022, 15, 1032. https://doi.org/10.3390/ph15081032

AMA Style

Wu D, Duan Q. Roles of Bromodomain Extra Terminal Proteins in Metabolic Signaling and Diseases. Pharmaceuticals. 2022; 15(8):1032. https://doi.org/10.3390/ph15081032

Chicago/Turabian Style

Wu, Dayu, and Qiong Duan. 2022. "Roles of Bromodomain Extra Terminal Proteins in Metabolic Signaling and Diseases" Pharmaceuticals 15, no. 8: 1032. https://doi.org/10.3390/ph15081032

APA Style

Wu, D., & Duan, Q. (2022). Roles of Bromodomain Extra Terminal Proteins in Metabolic Signaling and Diseases. Pharmaceuticals, 15(8), 1032. https://doi.org/10.3390/ph15081032

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop