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https://www.readbyqxmd.com/read/28933601/transcriptional-regulation-of-autophagy-and-lysosomal-function-by-bromodomain-protein-brd4
#1
Jun-Ichi Sakamaki, Kevin M Ryan
Macroautophagy/autophagy is an intracellular recycling system that delivers cytoplasmic organelles and materials to lysosomes for degradation. This process is operated by autophagy-related (ATG) genes and tightly controlled by stress-responsive signaling pathways. Our recent study revealed that autophagy programs are transcriptionally suppressed by the BET family protein BRD4. This repression is alleviated during nutrient deprivation through the AMPK-SIRT1 pathway. Our findings therefore provide new insights into the regulation of autophagy...
September 21, 2017: Autophagy
https://www.readbyqxmd.com/read/28931940/brd4-regulates-adiponectin-gene-induction-by-recruiting-the-p-tefb-complex-to-the-transcribed-region-of-the-gene
#2
Naoko Sakurai, Yuko Inamochi, Takuya Inoue, Natsuyo Hariya, Musashi Kawamura, Masami Yamada, Anup Dey, Akira Nishiyama, Takeo Kubota, Keiko Ozato, Toshinao Goda, Kazuki Mochizuki
We previously reported that induction of the adipocyte-specific gene adiponectin (Adipoq) during 3T3-L1 adipocyte differentiation is closely associated with epigenetic memory histone H3 acetylation on the transcribed region of the gene. We used 3T3-L1 adipocytes and Brd4 heterozygous mice to investigate whether the induction of Adipoq during adipocyte differentiation is regulated by histone acetylation and the binding protein bromodomain containing 4 (BRD4) on the transcribed region. Depletion of BRD4 by shRNA and inhibition by (+)-JQ1, an inhibitor of BET family proteins including BRD4, reduced Adipoq expression and lipid droplet accumulation in 3T3-L1 adipocytes...
September 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28930680/systematic-kinase-inhibitor-profiling-identifies-cdk9-as-a-synthetic-lethal-target-in-nut-midline-carcinoma
#3
Johannes Brägelmann, Marcel A Dammert, Felix Dietlein, Johannes M Heuckmann, Axel Choidas, Stefanie Böhm, André Richters, Debjit Basu, Verena Tischler, Carina Lorenz, Peter Habenberger, Zhizhou Fang, Sandra Ortiz-Cuaran, Frauke Leenders, Jan Eickhoff, Uwe Koch, Matthäus Getlik, Martin Termathe, Muhammad Sallouh, Zoltán Greff, Zoltán Varga, Hyatt Balke-Want, Christopher A French, Martin Peifer, H Christian Reinhardt, László Örfi, György Kéri, Sascha Ansén, Lukas C Heukamp, Reinhard Büttner, Daniel Rauh, Bert M Klebl, Roman K Thomas, Martin L Sos
Kinase inhibitors represent the backbone of targeted cancer therapy, yet only a limited number of oncogenic drivers are directly druggable. By interrogating the activity of 1,505 kinase inhibitors, we found that BRD4-NUT-rearranged NUT midline carcinoma (NMC) cells are specifically killed by CDK9 inhibition (CDK9i) and depend on CDK9 and Cyclin-T1 expression. We show that CDK9i leads to robust induction of apoptosis and of markers of DNA damage response in NMC cells. While both CDK9i and bromodomain inhibition over time result in reduced Myc protein expression, only bromodomain inhibition induces cell differentiation and a p21-induced cell-cycle arrest in these cells...
September 19, 2017: Cell Reports
https://www.readbyqxmd.com/read/28927100/hsa-mir-599-suppresses-the-migration-and-invasion-by-targeting-brd4-in-breast-cancer
#4
Yonghui Wang, Yana Sui, Qinwei Zhu, Xiaomei Sui
Breast cancer is the second leading cause of cancer-associated mortality in females in the USA. Hsa-miR-599 was demonstrated to function as a tumour suppressor during cancer progression. However, the function and mechanism of the hsa-miR-599 in human breast cancer remain elusive. Thus, the aim of the present study was to investigate the potential role of hsa-miR-599 in breast cancer biology. The expression levels of hsa-miR-599 in 40 pairs of surgical specimens and human breast cancer cell lines were detected using quantitative polymerase chain reaction analysis...
September 2017: Oncology Letters
https://www.readbyqxmd.com/read/28901664/pharmacophore-based-virtual-screening-molecular-docking-molecular-dynamics-simulation-and-biological-evaluation-for-the-discovery-of-novel-brd4-inhibitors
#5
Guoyi Yan, Manzhou Hou, Jiang Luo, Chunlan Pu, Xueyan Hou, Suke Lan, Rui Li
Bromodomain is a recognition module in the signal transduction of acetylated histone. BRD4, one of the bromodomain members, is emerging as an attractive therapeutic target for several types of cancer. Therefore, in this study an attempt has been made to screen compounds from an integrated database containing 5.5 million compounds for BRD4 inhibitors by using pharmacophore based virtual screening, molecular docking, and molecular dynamics simulations. As a result, two molecules out of twelve hits were found to be active in bioactivity tests...
September 13, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28892380/gne-781-a-highly-advanced-potent-and-selective-bromodomain-inhibitor-of-cyclic-adenosine-monophosphate-response-element-binding-protein-binding-protein-cbp
#6
F Anthony Romero, Jeremy Murray, Kwong Wah Lai, Vickie Tsui, Brian K Albrecht, Le An, Maureen H Beresini, Gladys de Leon Boenig, Sarah M Bronner, Emily W Chan, Kevin X Chen, Zhongguo Chen, Edna F Choo, Kyle Clagg, Kevin Clark, Terry D Crawford, Patrick Cyr, Denise de Almeida Nagata, Karen E Gascoigne, Jane L Grogan, Georgia Hatzivassiliou, Wei Huang, Thomas L Hunsaker, Susan Kaufman, Stefan G Koenig, Ruina Li, Yingjie Li, Xiaorong Liang, Jiangpeng Liao, Wenfeng Liu, Justin Ly, Jonathan Maher, Colin Masui, Mark Merchant, Yingqing Ran, Alexander M Taylor, John Wai, Fei Wang, Xiaocang Wei, Dong Yu, Bing-Yan Zhu, Xiaoyu Zhu, Steven Magnuson
Inhibition of the bromodomain of the transcriptional regulator CBP/P300 is an especially interesting new therapeutic approach in oncology. We recently disclosed in vivo chemical tool 1 (GNE-272) for the bromodomain of CBP that was moderately potent and selective over BRD4(1). In pursuit of a more potent and selective CBP inhibitor, we used structure-based design. Constraining the aniline of 1 into a tetrahydroquinoline motif maintained potency and increased selectivity 2-fold. Structure-activity relationship studies coupled with further structure-based design targeting the LPF shelf, BC loop, and KAc regions allowed us to significantly increase potency and selectivity, resulting in the identification of non-CNS penetrant 19 (GNE-781, TR-FRET IC50 = 0...
September 21, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28884163/identification-of-a-novel-class-of-brd4-inhibitors-by-computational-screening-and-binding-simulations
#7
Bryce K Allen, Saurabh Mehta, Stuart W J Ember, Jin-Yi Zhu, Ernst Schönbrunn, Nagi G Ayad, Stephan C Schürer
Computational screening is a method to prioritize small-molecule compounds based on the structural and biochemical attributes built from ligand and target information. Previously, we have developed a scalable virtual screening workflow to identify novel multitarget kinase/bromodomain inhibitors. In the current study, we identified several novel N-[3-(2-oxo-pyrrolidinyl)phenyl]-benzenesulfonamide derivatives that scored highly in our ensemble docking protocol. We quantified the binding affinity of these compounds for BRD4(BD1) biochemically and generated cocrystal structures, which were deposited in the Protein Data Bank...
August 31, 2017: ACS Omega
https://www.readbyqxmd.com/read/28881723/association-of-high-microvessel-%C3%AE-v%C3%AE-3-and-low-pten-with-poor-outcome-in-stage-3-neuroblastoma-rationale-for-using-first-in-class-dual-pi3k-brd4-inhibitor-sf1126
#8
Anat Erdreich-Epstein, Alok R Singh, Shweta Joshi, Francisco M Vega, Pinzheng Guo, Jingying Xu, Susan Groshen, Wei Ye, Melissa Millard, Mihaela Campan, Guillermo Morales, Joseph R Garlich, Peter W Laird, Robert C Seeger, Hiroyuki Shimada, Donald L Durden
Neuroblastoma (NB) is the most common extracranial solid tumor in children. Our previous studies showed that the angiogenic integrin αvβ3 was increased in high-risk metastatic (stage 4) NB compared with localized neuroblastomas. Herein, we show that integrin αvβ3 was expressed on 68% of microvessels in MYCN-amplified stage 3 neuroblastomas, but only on 34% (means) in MYCN-non-amplified tumors (p < 0.001; n = 54). PTEN, a tumor suppressor involved in αvβ3 signaling, was expressed in neuroblastomas either diffusely, focally or not at all (immunohistochemistry)...
August 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28881673/bromodomain-inhibition-shows-antitumoral-activity-in-mice-and-human-luminal-breast-cancer
#9
Montserrat Pérez-Salvia, Laia Simó-Riudalbas, Pere Llinàs-Arias, Laura Roa, Fernando Setien, Marta Soler, Manuel Castro de Moura, James E Bradner, Eva Gonzalez-Suarez, Catia Moutinho, Manel Esteller
BET bromodomain inhibitors, which have an antitumoral effect against various solid cancer tumor types, have not been studied in detail in luminal breast cancer, despite the prevalence of this subtype of mammary malignancy. Here we demonstrate that the BET bromodomain inhibitor JQ1 exerts growth-inhibitory activity in human luminal breast cancer cell lines associated with a depletion of the C-MYC oncogene, but does not alter the expression levels of the BRD4 bromodomain protein. Interestingly, expression microarray analyses indicate that, upon JQ1 administration, the antitumoral phenotype also involves downregulation of relevant breast cancer oncogenes such as the Breast Carcinoma-Amplified Sequence 1 (BCAS1) and the PDZ Domain-Containing 1 (PDZK1)...
August 1, 2017: Oncotarget
https://www.readbyqxmd.com/read/28881656/brd4-facilitates-dna-damage-response-and-represses-cbx5-heterochromatin-protein-1-hp1
#10
Georgios Pongas, Marianne K Kim, Dong J Min, Carrie D House, Elizabeth Jordan, Natasha Caplen, Sirisha Chakka, Joyce Ohiri, Michael J Kruhlak, Christina M Annunziata
Ovarian cancer (OC) is a heterogeneous disease characterized by defective DNA repair. Very few targets are universally expressed in the high grade serous (HGS) subtype. We previously identified that CHK1 was overexpressed in most of HGSOC. Here, we sought to understand the DNA damage response (DDR) to CHK1 inhibition and increase the anti-tumor activity of this pathway. We found BRD4 suppression either by siRNA or BRD4 inhibitor JQ1 enhanced the cytotoxicity of CHK1 inhibition. Interestingly, BRD4 was amplified and/or upregulated in a subset of HGSOC with statistical correlation to overall survival...
August 1, 2017: Oncotarget
https://www.readbyqxmd.com/read/28870238/bet-bromodomain-inhibitors-and-agonists-of-the-beta-2-adrenergic-receptor-identified-in-screens-for-compounds-that-inhibit-dux4-expression-in-fshd-muscle-cells
#11
Amy E Campbell, Jonathan Oliva, Matthew P Yates, Jun Wen Zhong, Sean C Shadle, Lauren Snider, Nikita Singh, Shannon Tai, Yosuke Hiramuki, Rabi Tawil, Silvère M van der Maarel, Stephen J Tapscott, Francis M Sverdrup
BACKGROUND: Facioscapulohumeral dystrophy (FSHD) is a progressive muscle disease caused by mutations that lead to epigenetic derepression and inappropriate transcription of the double homeobox 4 (DUX4) gene in skeletal muscle. Drugs that enhance the repression of DUX4 and prevent its expression in skeletal muscle cells therefore represent candidate therapies for FSHD. METHODS: We screened an aggregated chemical library enriched for compounds with epigenetic activities and the Pharmakon 1600 library composed of compounds that have reached clinical testing to identify molecules that decrease DUX4 expression as monitored by the levels of DUX4 target genes in FSHD patient-derived skeletal muscle cell cultures...
September 4, 2017: Skeletal Muscle
https://www.readbyqxmd.com/read/28862840/discovery-of-inhibitors-of-four-bromodomains-by-fragment-anchored-ligand-docking
#12
Jean-Rémy Marchand, Andrea Dalle Vedove, Graziano Lolli, Amedeo Caflisch
The high-throughput docking protocol called ALTA-VS (anchor-based library tailoring approach for virtual screening) was developed in 2005 for the efficient in silico screening of large libraries of compounds by preselection of only those molecules that have optimal fragments (anchors) for the protein target. Here we present an updated version of ALTA-VS with a broader range of potential applications. The evaluation of binding energy makes use of a classical force field with implicit solvent in the continuum dielectric approximation...
September 18, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28854735/brd4-inhibitors-block-telomere-elongation
#13
Steven Wang, Alexandra M Pike, Stella S Lee, Margaret A Strong, Carla J Connelly, Carol W Greider
Cancer cells maintain telomere length equilibrium to avoid senescence and apoptosis induced by short telomeres, which trigger the DNA damage response. Limiting the potential for telomere maintenance in cancer cells has been long been proposed as a therapeutic target. Using an unbiased shRNA screen targeting known kinases, we identified bromodomain-containing protein 4 (BRD4) as a telomere length regulator. Four independent BRD4 inhibitors blocked telomere elongation, in a dose-dependent manner, in mouse cells overexpressing telomerase...
August 21, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28851877/vegf-amplifies-transcription-through-ets1-acetylation-to-enable-angiogenesis
#14
Jiahuan Chen, Yi Fu, Daniel S Day, Ye Sun, Shiyan Wang, Xiaodong Liang, Fei Gu, Fang Zhang, Sean M Stevens, Pingzhu Zhou, Kai Li, Yan Zhang, Ruei-Zeng Lin, Lois E H Smith, Jin Zhang, Kun Sun, Juan M Melero-Martin, Zeguang Han, Peter J Park, Bing Zhang, William T Pu
Release of promoter-proximally paused RNA polymerase II (RNAPII) is a recently recognized transcriptional regulatory checkpoint. The biological roles of RNAPII pause release and the mechanisms by which extracellular signals control it are incompletely understood. Here we show that VEGF stimulates RNAPII pause release by stimulating acetylation of ETS1, a master endothelial cell transcriptional regulator. In endothelial cells, ETS1 binds transcribed gene promoters and stimulates their expression by broadly increasing RNAPII pause release...
August 29, 2017: Nature Communications
https://www.readbyqxmd.com/read/28846832/induction-of-a-novel-isoform-of-the-lncrna-hotair-in-claudin-low-breast-cancer-cells-attached-to-extracellular-matrix
#15
Miao Li, Xi Li, Yan Zhuang, Erik K Flemington, Lin Zhen, Bin Shan
Elevated overexpression of the lncRNA HOTAIR mediates invasion and metastasis in breast cancer. In an apparent paradox, we observed low expression of HOTAIR in the invasive Claudin-low MDA-MB-231 and Hs578T cells in two-dimensional culture (2D). However, HOTAIR expression exhibited robust induction in laminin-rich extracellular matrix based three-dimensional organotypic culture (lrECM 3D) over that in 2D culture. Induction of HOTAIR required intact ECM signaling, namely integrin α2 and SRC kinase activity...
August 28, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/28844955/brd4-has-dual-effects-on-the-hmgb1-and-nf-%C3%AE%C2%BAb-signalling-pathways-and-is-a-potential-therapeutic-target-for-osteoarthritis
#16
Jiang Yafei, Zhu Libo, Zhang Tao, Lu Haiming, Wang Cong, Xue Bao, Xu Xun, Liu Yu, Cai Zhengdong, Sang Weilin, Hua Yingqi, Ma Jinzhong
Osteoarthritis (OA) has traditionally been defined as a non-inflammatory disease. Recently, many studies have demonstrated that OA also has an inflammatory component. BRD4, a member of the Bromodomain and Extra-Terminal Domain family, has emerged as an important regulator of some chronic inflammatory diseases. JQ1, an antagonist of BRD4, modulates transcription of several genes. Our study demonstrated that BRD4 is up-regulated in articular cartilage of OA. BRD4 inhibition attenuated the inflammation and catabolism of chondrocytes and suppressed NF-κB signalling pathway activation...
August 24, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28844864/the-short-isoform-of-brd4-promotes-hiv-1-latency-by-engaging-repressive-swi-snf-chromatin-remodeling-complexes
#17
Ryan J Conrad, Parinaz Fozouni, Sean Thomas, Hendrik Sy, Qiang Zhang, Ming-Ming Zhou, Melanie Ott
BET proteins commonly activate cellular gene expression, yet inhibiting their recruitment paradoxically reactivates latent HIV-1 transcription. Here we identify the short isoform of BET family member BRD4 (BRD4S) as a corepressor of HIV-1 transcription. We found that BRD4S was enriched in chromatin fractions of latently infected T cells, and it was more rapidly displaced from chromatin upon BET inhibition than the long isoform. BET inhibition induced marked nucleosome remodeling at the latent HIV-1 promoter, which was dependent on the activity of BRG1-associated factors (BAF), an SWI/SNF chromatin-remodeling complex with known repressive functions in HIV-1 transcription...
August 17, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28837371/brd4-is-a-newly-characterized-transcriptional-regulator-that-represses-autophagy-and-lysosomal-function
#18
Xin Wen, Daniel J Klionsky
As a member of the bromodomain and extraterminal (BET) family, BRD4 (bromodomain containing 4) can bind to acetylated histones and transcription factors, and is also able to recruit various transcriptional regulators. Previous studies have shown that BRD4 mainly plays a positive role in cell growth and cell cycle progression. In a recent study conducted by Sakamaki et al., the authors found that BRD4 acts as a transcriptional repressor in regulating macroautophagy/autophagy and lysosome gene expression, via binding to the histone lysine methyltransferase EHMT2/G9a...
August 24, 2017: Autophagy
https://www.readbyqxmd.com/read/28837236/renal-nut-carcinoma-a-case-report
#19
Deepika Sirohi, Karuna Garg, Jeffry P Simko, James P Grenert
Nuclear protein in testis (NUT)-midline carcinomas were first described more than two decades ago with characteristic reciprocal translocations involving BRD4 on chromosomes 15 and NUTM1 on chromosome 19 (1). Over the years, these tumors have been reported in non-midline locations as well as outside of the upper aerodigestive tract and mediastinum. We recently encountered a renal NUT carcinoma (NC) diagnosed next generation sequencing (NGS) that is reported here. This article is protected by copyright. All rights reserved...
August 24, 2017: Histopathology
https://www.readbyqxmd.com/read/28821780/selective-inhibition-mechanism-of-rvx-208-to-the-second-bromodomain-of-bromo-and-extraterminal-proteins-insight-from-microsecond-molecular-dynamics-simulations
#20
Qianqian Wang, Ying Li, Jiahui Xu, Yuwei Wang, Elaine Lai-Han Leung, Liang Liu, Xiaojun Yao
RVX-208 is a recently reported inhibitor of bromo and extraterminal (BET) family proteins (including BRD2-4 and BRDT) with selectivity for the second bromodomain (BD2), currently in phase III clinical trials. Despite of its promising antitumor activity, due to the conserved folds of the first and second bromodomains (BD1 and BD2), the detailed selectivity mechanism of RVX-208 towards BD2 over BD1 is still unknown. To elucidate selective inhibition mechanism of RVX-208 to BD2, microsecond molecular dynamics simulations were performed in this study for BRD2-BD1, BRD2-BD2 and BRD4-BD1 with and without RVX-208, respectively...
August 18, 2017: Scientific Reports
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