Редактирование: BRD4

Bromodomain-containing protein 4 (Protein HUNK1) [HUNK1]

==Publications==

{{medline-entry
|title=Inhibition of [[BRD4]] triggers cellular senescence through suppressing aurora kinases in oesophageal cancer cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32954665
|abstract=Oesophageal cancer is one of the most frequent solid malignancies and the leading cause of cancer-related death around the world. It is urgent to develop novel therapy strategies to improve patient outcomes. Acetylation modification of histones has been extensively studied in epigenetics. [[BRD4]], a reader of acetylated histone and non-histone proteins, has involved in tumorigenesis. It has emerged as a promising target for cancer therapy. [[BRD4]] inhibitors, such as JQ1, have exerted efficacious anti-proliferation activities in diverse cancers. However, the effects of JQ1 on oesophageal cancer are still not fully described. Here, we demonstrate that JQ1 suppresses cell growth and triggers cellular senescence in KYSE450 cells. Mechanistically, JQ1 up-regulates p21 level and decreases cyclin D1 resulting in G1 cycle arrest. The inhibitory effects of JQ1 on KYSE450 cells are independent on apoptosis. It activates cellular senescence by increasing SA-β-gal activity. [[BRD4]] knockdown by shRNA recapitulates cellular senescence. We also display that administration of JQ1 decreases recruitment of [[BRD4]] on the promoter of aurora kinases A and B. Inhibitors targeting at AURKA/B phenocopy JQ1 treatment in KYSE450 cells. These results identify a novel action manner of [[BRD4]] in oesophageal cancer, which strengthens JQ1 as a candidate drug in oesophageal cancer chemotherapy.

|keywords=* BRD4
* aurora kinase
* cellular senescence
* oesophageal cancer
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7701500
}}
{{medline-entry
|title=[[BRD4]] contributes to LPS-induced macrophage senescence and promotes progression of atherosclerosis-associated lipid uptake.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32392533
|abstract=Aging is closely associated with atherosclerosis. Macrophages accumulate in atherosclerotic lesions contributing to the development and progression of atherosclerosis. Although atherosclerotic lesions are known to contain senescent cells, the mechanism underlying the formation of senescent macrophages during atherosclerosis is still unclear. In this study, macrophages with different origins were collected, including THP-1 macrophages, telomerase reverse transcriptase knock out (Tert ) mouse peritoneal macrophages, and human peripheral blood mononuclear cells (PBMCs). We found Lipopolysaccharide (LPS) could induce the formation of senescent macrophages, which was typified by the morphological changes, senescence-associated secretory phenotype (SASP) secretory, and persistent DNA damage response. Mechanistically, bromodomain-containing protein 4 ([[BRD4]]), a chromosomal binding protein related to gene expression, was found to play a key role in the pathological process, which could offer new therapeutic perspectives. Inhibition of [[BRD4]] by si[[BRD4]] or inhibitors such as JQ-1 or I-BET762 prevented the aging of macrophages and lipid accumulation in the LPS-induced senescent macrophages by decreasing expression of SASP in autocrine and paracrine senescence. These findings have significant implications for the understanding of the pathobiology of age-associated diseases and may guide future studies on targeted clinical drug therapy.

|keywords=* BRD4
* gene expression
* inflammation
* macrophage
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288959
}}
{{medline-entry
|title=BET Proteins Are Required for Transcriptional Activation of the Senescent Islet Cell Secretome in Type 1 Diabetes.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31561444
|abstract=Type 1 diabetes (T1D) results from the progressive loss of pancreatic beta cells as a result of autoimmune destruction. We recently reported that during the natural history of T1D in humans and the female nonobese diabetic (NOD) mouse model, beta cells acquire a senescence-associated secretory phenotype (SASP) that is a major driver of disease onset and progression, but the mechanisms that activate SASP in beta cells were not explored. Here, we show that the SASP in islet cells is transcriptionally controlled by Bromodomain ExtraTerminal (BET) proteins, including Bromodomain containing protein 4 ([[BRD4]]). A chromatin analysis of key beta cell SASP genes in NOD islets revealed binding of [[BRD4]] at active regulatory regions. BET protein inhibition in NOD islets diminished not only the transcriptional activation and secretion of SASP factors, but also the non-cell autonomous activity. BET protein inhibition also decreased the extent of SASP induction in human islets exposed to DNA damage. The BET protein inhibitor iBET-762 prevented diabetes in NOD mice and also attenuated SASP in islet cells in vivo. Taken together, our findings support a crucial role for BET proteins in the activation of the SASP transcriptional program in islet cells. These studies suggest avenues for preventing T1D by transcriptional inhibition of SASP.
|mesh-terms=* Animals
* Cell Cycle Proteins
* Cellular Senescence
* Diabetes Mellitus, Type 1
* Female
* Humans
* Insulin-Secreting Cells
* Islets of Langerhans
* Mice
* Mice, Inbred NOD
* Paracrine Communication
* Protein Binding
* Transcription Factors
* Transcriptional Activation
|keywords=* BET proteins
* beta cells
* senescence and SASP
* type 1 diabetes
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6801956
}}
{{medline-entry
|title=Interference with the bromodomain epigenome readers drives p21 expression and tumor senescence.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31265875
|abstract=Head and neck cancer (HNSCC) are one of the most common solid malignancies of the world, being responsible for over 350,000 deaths every year. Much of the complications in managing and treating HNSCC advent from the complex genetic and epigenetic landscape of the disease. Emerging information has shown promising results in targeting [[BRD4]], an epigenetic regulator bromodomain that functions as a scaffold for transcription factors at promoters and super-enhancers. Here we show that by disrupting the interaction between [[BRD4]] and histones using the bromodomain inhibitor JQ1, HNSCC cells undergo cell growth arrest followed by cellular senescence. Mechanistically, JQ1 negatively impacted the phosphorylation levels of [[SIRT1]] along with the acetylation levels of mutant p53 (active). In vivo administration of JQ1 resulted in disruption of HNSCC growth along with the activation of cellular senescence, observed by the accumulation of DNA double-strand breaks, p16 , accumulation of senescence-associated beta-galactosidase, and loss of phosphorylated Sirt1 . Furthermore, we also demonstrate that JQ1 was efficient in reducing the population of cancer stem cells from HNSCC xenografts.
|mesh-terms=* Animals
* Apoptosis
* Azepines
* Biomarkers, Tumor
* Cell Cycle
* Cell Cycle Proteins
* Cell Proliferation
* Cellular Senescence
* Cyclin-Dependent Kinase Inhibitor p21
* Epigenome
* Female
* Gene Expression Regulation, Neoplastic
* Head and Neck Neoplasms
* Histones
* Humans
* Mice
* Mice, Nude
* Neoplastic Stem Cells
* Prognosis
* Squamous Cell Carcinoma of Head and Neck
* Survival Rate
* Transcription Factors
* Triazoles
* Tumor Cells, Cultured
* Xenograft Model Antitumor Assays
|keywords=* Cancer stem cell
* Head and neck cancer
* Senescence
* Tumor suppression
* Xenograft
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7159039
}}
{{medline-entry
|title=Neuroprotective effects of targeting BET proteins for degradation with dBET1 in aged mice subjected to ischemic stroke.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30872008
|abstract=Neuroinflammation after stroke significantly contributes to neuronal cell death. Bromodomain and Extra Terminal Domain (BET) proteins are essential to inflammatory gene transcription. BET proteins (BRD2, [[BRD3]], [[BRD4]], and BRDT) have varied effects including chromatin remodeling, histone acetyltransferase activity, and as scaffolds to recruit transcription factors; they couple chromatin remodeling with transcription. BRD2/4 are of particularly interest to stroke-induced neuroinflammation that contributes to delayed cell death as they are required for NF-κB-dependent gene transcription. We hypothesized that targeting BET proteins for degradation with dBET1, a proteolysis targeting chimera (PROTAC) that combines the highly selective BET inhibitor JQ1 and a ligand for cereblon E3 ubiquitin ligase, will reduce brain injury in ischemic stroke. Male aged mice (18-20 months old) were subjected to permanent occlusion of the middle cerebral artery and received either vehicle or dBET1 (10 mg/kg; i.p.) at various times after stroke. Neurobehavioral tests were performed before (baseline) and at 24 and 48 h after stroke induction. Infarct volume was quantified at 48 h. Data showed that BET degradation significantly reduced infarct volume in permanent focal cerebral ischemia in aged mice, and this was associated with reduced brain levels of pro-inflammatory mediators including [[TNF]]-α, [[CXCL1]], [[[[CXCL1]]0]], [[CCL2]], and matrix metalloproteinase-9. Treatment with dBET1 significantly reduced blood-brain barrier damage and infiltration of neutrophils into the ischemic brain. Importantly, treatment with the BET degrader dBET1 resulted in a significant improvement in stroke-induced neurological deficits. Collectively, these data indicate that BET proteins are a novel target for neuroprotection in ischemic stroke.
|mesh-terms=* Aging
* Animals
* Brain Injuries
* Brain Ischemia
* Disease Models, Animal
* Male
* Mice, Inbred C57BL
* Nerve Tissue Proteins
* Neuroprotective Agents
* Protein Transport
* Receptors, Cell Surface
* Stroke
* Transcription Factors
|keywords=* Aged mice
* BET proteins
* BRD4
* Ischemic stroke
* Neuroinflammation
* dBET1
|full-text-url=https://sci-hub.do/10.1016/j.neuint.2019.03.004
}}
{{medline-entry
|title=Bromodomain and Extraterminal Protein Inhibition Blocks Growth of Triple-negative Breast Cancers through the Suppression of Aurora Kinases.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27650498
|abstract=Bromodomain and extraterminal (BET) proteins are epigenetic "readers" that recognize acetylated histones and mark areas of the genome for transcription. [[BRD4]], a BET family member protein, has been implicated in a number of types of cancer, and BET protein inhibitors (BETi) are efficacious in many preclinical cancer models. However, the drivers of response to BETi vary depending on tumor type, and little is known regarding the target genes conveying BETi activity in triple-negative breast cancer (TNBC). Here, we show that BETi repress growth of multiple in vitro and in vivo models of TNBC by inducing two terminal responses: apoptosis and senescence. Unlike in other cancers, response to BETi in TNBC is not dependent upon suppression of [[MYC]] Instead, both end points are preceded by the appearance of polyploid cells caused by the suppression of Aurora kinases A and B (AURKA/B), which are critical mediators of mitosis. In addition, AURKA/B inhibitors phenocopy the effects of BETi. These results indicate that Aurora kinases play an important role in the growth suppressive activity of BETi in TNBC. Elucidating the mechanism of response to BETi in TNBC should 1) facilitate the prediction of how distinct TNBC tumors will respond to BETi and 2) inform the rational design of drug combination therapies.
|mesh-terms=* Animals
* Antineoplastic Agents
* Apoptosis
* Aurora Kinase A
* Aurora Kinase B
* Breast
* Cell Cycle Proteins
* Cell Line, Tumor
* Cell Proliferation
* Female
* Humans
* Mice
* Mice, Inbred NOD
* Mice, SCID
* Nuclear Proteins
* Protein Kinase Inhibitors
* Transcription Factors
* Triple Negative Breast Neoplasms
|keywords=* Aurora kinase
* anticancer drug
* apoptosis
* breast cancer
* bromodomain-containing protein 4 (BRD4)
* cellular senescence
* inhibition mechanism
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5095428
}}