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Bromodomain

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https://www.readbyqxmd.com/read/28815970/structural-insight-into-cbp-bromodomain-mediated-recognition-of-acetylated-histone-h3k56ac
#1
Li Xu, Aimin Cheng, Min Huang, Jiahai Zhang, Yiyang Jiang, Chongyuan Wang, Fudong Li, Hongyu Bao, Jia Gao, Na Wang, Jiuyang Liu, Jihui Wu, Catherine C L Wong, Ke Ruan
The acetylation of lysine 56 of histone H3 (H3K56ac) enhances the binding affinity of histone chaperones to H3-H4 dimers. CREB binding protein (CBP) possesses a bromodomain that recognizes H3K56 acetylation. CBP also possesses a histone acetyltransferase (HAT) domain, which has been shown to promote H3K56 acetylation of free histones to facilitate delivery of replication-dependent chaperones to acetylated histones for chromatin assembly. However, the mechanism by which the CBP bromodomain recognizes H3K56ac, and thecontext in which such recognition occurs remains elusive...
August 16, 2017: FEBS Journal
https://www.readbyqxmd.com/read/28813519/expression-and-inhibition-of-brd4-ezh2-and-top2a-in-neurofibromas-and-malignant-peripheral-nerve-sheath-tumors
#2
Azadeh Amirnasr, Rob M Verdijk, Patricia F van Kuijk, Walter Taal, Stefan Sleijfer, Erik A C Wiemer
Malignant peripheral nerve sheath tumors (MPNST) are rare, highly aggressive sarcomas that can occur spontaneously or from pre-existing plexiform neurofibromas in neurofibromatosis type1 (NF1) patients. MPNSTs have high local recurrence rates, metastasize easily, are generally resistant to therapeutic intervention and frequently fatal for the patient. Novel targeted therapeutic strategies are urgently needed. Standard treatment for patients presenting with advanced disease is doxorubicin based chemotherapy which inhibits the actions of the enzyme topoisomerase IIα (TOP2A)...
2017: PloS One
https://www.readbyqxmd.com/read/28807940/mitotic-vulnerability-in-triple-negative-breast-cancer-associated-with-lin9-is-targetable-with-bet-inhibitors
#3
Jennifer M Sahni, Sylvia S Gayle, Bryan Webb, Kristen L Weber-Bonk, Darcie D Seachrist, Salendra Singh, Steven T Sizemore, Nicole A Restrepo, Gurkan Bebek, Peter Scacheri, Vinay Varadan, Matthew K Summers, Ruth A Keri
Triple-negative breast cancers (TNBC) are highly aggressive, lack FDA-approved targeted therapies, and frequently recur, making the discovery of novel therapeutic targets for this disease imperative. Our previous analysis of the molecular mechanisms of action of Bromodomain and extraterminal protein inhibitors (BETi) in TNBC revealed these drugs cause multinucleation, indicating BET proteins are essential for efficient mitosis and cytokinesis. Here, using live cell imaging, we show that BET inhibition prolonged mitotic progression and induced mitotic cell death, both of which are indicative of mitotic catastrophe...
August 14, 2017: Cancer Research
https://www.readbyqxmd.com/read/28806224/bromodomain-containing-protein-4-activates-voltage-gated-sodium-channel-1-7-transcription-in-dorsal-root-ganglia-neurons-to-mediate-thermal-hyperalgesia-in-rats
#4
Ming-Chun Hsieh, Yu-Cheng Ho, Cheng-Yuan Lai, Hsueh-Hsiao Wang, An-Sheng Lee, Jen-Kun Cheng, Yat-Pang Chau, Hsien-Yu Peng
BACKGROUND: Bromodomain-containing protein 4 binds acetylated promoter histones and promotes transcription; however, the role of bromodomain-containing protein 4 in inflammatory hyperalgesia remains unclear. METHODS: Male Sprague-Dawley rats received hind paw injections of complete Freund's adjuvant to induce hyperalgesia. The dorsal root ganglia were examined to detect changes in bromodomain-containing protein 4 expression and the activation of genes involved in the expression of voltage-gated sodium channel 1...
August 11, 2017: Anesthesiology
https://www.readbyqxmd.com/read/28805822/intrinsic-bet-inhibitor-resistance-in-spop-mutated-prostate-cancer-is-mediated-by-bet-protein-stabilization-and-akt-mtorc1-activation
#5
Pingzhao Zhang, Dejie Wang, Yu Zhao, Shancheng Ren, Kun Gao, Zhenqing Ye, Shangqian Wang, Chun-Wu Pan, Yasheng Zhu, Yuqian Yan, Yinhui Yang, Di Wu, Yundong He, Jun Zhang, Daru Lu, Xiuping Liu, Long Yu, Shimin Zhao, Yao Li, Dong Lin, Yuzhuo Wang, Liguo Wang, Yu Chen, Yinghao Sun, Chenji Wang, Haojie Huang
Bromodomain and extraterminal domain (BET) protein inhibitors are emerging as promising anticancer therapies. The gene encoding the E3 ubiquitin ligase substrate-binding adaptor speckle-type POZ protein (SPOP) is the most frequently mutated in primary prostate cancer. Here we demonstrate that wild-type SPOP binds to and induces ubiquitination and proteasomal degradation of BET proteins (BRD2, BRD3 and BRD4) by recognizing a degron motif common among them. In contrast, prostate cancer-associated SPOP mutants show impaired binding to BET proteins, resulting in decreased proteasomal degradation and accumulation of these proteins in prostate cancer cell lines and patient specimens and causing resistance to BET inhibitors...
August 14, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28805820/prostate-cancer-associated-spop-mutations-confer-resistance-to-bet-inhibitors-through-stabilization-of-brd4
#6
Xiangpeng Dai, Wenjian Gan, Xiaoning Li, Shangqian Wang, Wei Zhang, Ling Huang, Shengwu Liu, Qing Zhong, Jianping Guo, Jinfang Zhang, Ting Chen, Kouhei Shimizu, Francisco Beca, Mirjam Blattner, Divya Vasudevan, Dennis L Buckley, Jun Qi, Lorenz Buser, Pengda Liu, Hiroyuki Inuzuka, Andrew H Beck, Liewei Wang, Peter J Wild, Levi A Garraway, Mark A Rubin, Christopher E Barbieri, Kwok-Kin Wong, Senthil K Muthuswamy, Jiaoti Huang, Yu Chen, James E Bradner, Wenyi Wei
The bromodomain and extraterminal (BET) family of proteins comprises four members-BRD2, BRD3, BRD4 and the testis-specific isoform BRDT-that largely function as transcriptional coactivators and play critical roles in various cellular processes, including the cell cycle, apoptosis, migration and invasion. BET proteins enhance the oncogenic functions of major cancer drivers by elevating the expression of these drivers, such as c-Myc in leukemia, or by promoting the transcriptional activities of oncogenic factors, such as AR and ERG in prostate cancer...
August 14, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28804523/tri-methylation-of-h3k79-is-decreased-in-tgf-%C3%AE-1-induced-epithelial-to-mesenchymal-transition-in-lung-cancer
#7
Emilie Evanno, Julie Godet, Nathalie Piccirilli, Joëlle Guilhot, Serge Milin, Jean Marc Gombert, Benoit Fouchaq, Joëlle Roche
BACKGROUND: The epithelial-to-mesenchymal transition (EMT) enables epithelial cancer cells to acquire mesenchymal features and contributes to metastasis and resistance to treatment. This process involves epigenetic reprogramming for gene expression. We explored global histone modifications during TGF-β1-induced EMT in two non-small cell lung cancer (NSCLC) cell lines and tested different epigenetic treatment to modulate or partially reverse EMT. RESULTS: Loss of classical epithelial markers and gain of mesenchymal markers were verified in A549 and H358 cell lines during TGF-β1-induced EMT...
2017: Clinical Epigenetics
https://www.readbyqxmd.com/read/28798233/the-atad2-bromodomain-binds-different-acetylation-marks-on-the-histone-h4-in-similar-fuzzy-complexes
#8
Cassiano Langini, Amedeo Caflisch, Andreas Vitalis
Bromodomains are protein modules adopting conserved helix-bundle folds. Some bromodomain-containing proteins, such as ATPase family AAA domain-containing protein 2 (ATAD2), isoform A, have attracted much interest because they are overexpressed in many types of cancer. Bromodomains bind to acetylated lysine residues on histone tails and thereby facilitate the reading of the histone code. Epigenetic regulators in general have been implicated as indicators, mediators, or causes of a large number of diseases and disorders...
August 10, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28796244/bet-bromodomain-inhibitors-synergize-with-atr-inhibitors-in-melanoma-in-melanoma
#9
Somsundar Veppil Muralidharan, Berglind Osk Einarsdottir, Joydeep Bhadury, Mattias F Lindberg, Jin Wu, Eric Campeau, Roger Olofsson Bagge, Ulrika Stierner, Lars Ny, Lisa M Nilsson, Jonas A Nilsson
Metastatic malignant melanoma continues to be a challenging disease despite clinical translation of the comprehensive understanding of driver mutations and how melanoma cells evade immune attack. In Myc-driven lymphoma, efficacy of epigenetic inhibitors of the bromodomain and extra-terminal domain (BET) family of bromodomain proteins can be enhanced by combination therapy with inhibitors of the DNA damage response kinase ATR. Whether this combination is active in solid malignancies like melanoma, and how it relates to immune therapy, has not previously investigated...
August 10, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28783698/maintenance-of-macrophage-transcriptional-programs-and-intestinal-homeostasis-by-epigenetic-reader-sp140
#10
Stuti Mehta, D Alexander Cronkite, Megha Basavappa, Tahnee L Saunders, Fatemeh Adiliaghdam, Hajera Amatullah, Sara A Morrison, Jose D Pagan, Robert M Anthony, Pierre Tonnerre, Georg M Lauer, James C Lee, Sreehaas Digumarthi, Lorena Pantano, Shannan J Ho Sui, Fei Ji, Ruslan Sadreyev, Chan Zhou, Alan C Mullen, Vinod Kumar, Yang Li, Cisca Wijmenga, Ramnik J Xavier, Terry K Means, Kate L Jeffrey
Epigenetic "readers" that recognize defined posttranslational modifications on histones have become desirable therapeutic targets for cancer and inflammation. SP140 is one such bromodomain- and plant homeodomain (PHD)-containing reader with immune-restricted expression, and single-nucleotide polymorphisms (SNPs) within SP140 associate with Crohn's disease (CD). However, the function of SP140 and the consequences of disease-associated SP140 SNPs have remained unclear. We show that SP140 is critical for transcriptional programs that uphold the macrophage state...
March 3, 2017: Science Immunology
https://www.readbyqxmd.com/read/28771339/specific-acetylation-patterns-of-h2a-z-form-transient-interactions-with-the-bptf-bromodomain
#11
Gabriella T Perell, Neeraj K Mishra, Babu Sudhamalla, Peter D Ycas, Kabirul Islam, William C K Pomerantz
Post-translational lysine acetylation of histone tails affect both chromatin accessibility and recruitment of multi-functional bromodomain-containing proteins for modulating transcription. Bromodomain and PHD finger-containing protein (BPTF) regulates transcription, but has also been implicated with high gene expression levels in a variety of cancers. In this report, the histone variant H2A.Z, which replaces H2A in chromatin, is evaluated for affinity towards BPTF with a specific recognition pattern of acetylated lysine residues of the N-terminal tail region...
August 3, 2017: Biochemistry
https://www.readbyqxmd.com/read/28766886/small-cell-lung-carcinoma-cell-line-screen-of-etoposide-carboplatin-plus-a-third-agent
#12
Beverly A Teicher, Thomas Silvers, Michael Selby, Rene Delosh, Julie Laudeman, Chad Ogle, Russell Reinhart, Ralph Parchment, Julia Krushkal, Dmitriy Sonkin, Larry Rubinstein, Joel Morris, David Evans
The SCLC combination screen examined a 9-point concentration response of 180 third agents, alone and in combination with etoposide/carboplatin. The predominant effect of adding a third agent to etoposide/carboplatin was additivity. Less than additive effects occurred frequently in SCLC lines sensitive to etoposide/carboplatin. In SCLC lines with little or no response to etoposide/carboplatin, greater than additive SCLC killing occurred over the entire spectrum of SCLC lines but never occurred in all SCLC lines...
August 2017: Cancer Medicine
https://www.readbyqxmd.com/read/28766825/beyond-the-bet-family-targeting-cbp-p300-with-4-acyl-pyrroles
#13
Martin Hügle, Xavier Lucas, Dmytro Ostrovskyi, Pierre Regenass, Stefan Gerhardt, Oliver Einsle, Mirjam Hau, Manfred Jung, Bernhard Breit, Stefan Günther, Daniel Wohlwend
BET bromodomain inhibitors are widely used both as chemical tools to study the biological role of their targets in living organisms, and as candidates for drug development against several cancer variants and human disorders. However, non-BET bromodomains such as those in p300 and CBP are less studied. Here, we introduce XDM-CBP, a highly potent and selective inhibitor for the bromodomains of CBP and p300 derived from a pan-selective BET BRD-binding fragment. In addition to X-ray crystal structure analysis and thermodynamic profiling, we used XDM-CBP in in vitro cell screenings of several cancer cell lines to study its inhibitory potential on cancer cell proliferation...
August 2, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28766687/downregulation-of-brd4-inhibits-gallbladder-cancer-proliferation-and-metastasis-and-induces-apoptosis-via-pi3k-akt-pathway
#14
Jiaqi Hao, Ziyi Yang, Lei Wang, Yijian Zhang, Yijun Shu, Lin Jiang, Yunping Hu, Wenjie Lv, Ping Dong, Yingbin Liu
Bromodomain containing protein 4 (BRD4) has been demonstrated to play a critical role in tumor progression. However, the expression and function of BRD4 in gallbladder cancer (GBC) are still unknown. In this study, we report that BRD4 expression level was significantly upregulated in GBC tissues and GBC cell lines. We explored the correlation between BRD4 levels and clinicopathological data of GBC patients. The high expression level of BRD4 was notably correlated with the poor prognosis of GBC patients. Knockdown of BRD4 suppressed proliferation and migration in NOZ and EH-GB1 cells...
September 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/28765013/structure-based-design-synthesis-and-in-vitro-antiproliferative-effects-studies-of-novel-dual-brd4-hdac-inhibitors
#15
Mingfeng Shao, Linhong He, Li Zheng, Lingxiao Huang, Yuanyuan Zhou, Taijing Wang, Yong Chen, Mingsheng Shen, Fang Wang, Zhuang Yang, Lijuan Chen
Histone acetylation marks play important roles in controlling gene expressions and are removed by histone deacetylases (HDACs). These marks are read by bromodomain and extra-terminal (BET) proteins, whose targeted inhibitors are under clinical investigation. BET and HDAC inhibitors have been demonstrated to be synergistically killing in Mycinduced murine lymphoma. Herein, we combine the inhibitory activities of BET and HDAC into one molecule through structure-based design method and evaluate its function. The majority of these synthesized compounds showed inhibitory activity against second bromdomains(BRD) of BRD4 and HDAC1...
July 21, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28758277/fusion-of-the-genes-brd8-and-phf1-in-endometrial-stromal-sarcoma
#16
Francesca Micci, Marta Brunetti, Paola Dal Cin, Marisa R Nucci, Ludmila Gorunova, Sverre Heim, Ioannis Panagopoulos
We present a new endometrial stromal sarcoma (ESS)-associated genomic rearrangement involving chromosome arms 5p and 6p and leading to the formation of a BRD8-PHF1 fusion gene. The PHF1 (PHD finger protein 1) gene, from 6p21, is known to be rearranged in ESS in a promiscuous way inasmuch as it has been shown to recombine with JAZF1, EPC1, MEAF6, and now also with BRD8, in tumors of this type. In all rearrangements of PHF1, including the present one, a recurrent theme is that the entire coding part of PHF1 constitutes the 3' end of the fusion...
July 30, 2017: Genes, Chromosomes & Cancer
https://www.readbyqxmd.com/read/28751557/the-bet-bromodomain-inhibitor-cpi203-improves-lenalidomide-and-dexamethasone-activity-in-in-vitro-and-in-vivo-models-of-multiple-myeloma-by-blockade-of-ikaros-and-myc-signaling
#17
Tania Díaz, Vanina Rodríguez, Ester Lozano, Mari-Pau Mena, Marcos Calderón, Laura Rosiñol, Antonio Martínez, Natalia Tovar, Patricia Pérez-Galán, Joan Bladé, Gaël Roué, Carlos Fernández de Larrea
Most of patients with multiple myeloma treated with current therapies, including immunomodulatory drugs, eventually develop relapsed/refractory disease. Clinical activity of lenalidomide relies on degradation of Ikaros and the consequently reduction on IRF4 expression, both required for myeloma cell survival and involved in the regulation of MYC transcription. Thus, we sought to determine the combinatorial effect of a MYC-interfering therapy with lenalidomide/dexamethasone. We analyzed the potential therapeutic effect of the combination of BET bromodomain inhibitor CPI203 with the lenalidomide/dexamethasone regimen in myeloma cell lines...
July 27, 2017: Haematologica
https://www.readbyqxmd.com/read/28750570/identification-of-potential-ibrutinib-combinations-in-hematological-malignancies-using-a-combination-high-throughput-screen
#18
Michael Schaffer, Shalini Chaturvedi, Cuc Davis, Regina Aquino, Emily Stepanchick, Matthias Versele, Yang Liu, Jennifer Yang, Rongzhen Lu, Sriram Balasubramanian
Matrix high-throughput screening (HTS) methods are increasingly employed to rapidly define potential therapeutic drug combinations. We used combination HTS to identify compounds showing synergistic anti-proliferative activity with ibrutinib, an irreversible, small-molecule inhibitor of Bruton's tyrosine kinase. The goal was to identify ibrutinib combinations with maximum synergistic effects in heme malignancy lines, particularly in non-Hodgkin lymphoma including diffuse large B-cell lymphoma (DLBCL). Growth inhibition (GI) was used to measure cell viability; synergy scores characterized strength of synergistic interaction...
July 28, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28747513/repression-of-bet-activity-sensitizes-homologous-recombination-proficient-cancers-to-parp-inhibition
#19
Lu Yang, Youyou Zhang, Weiwei Shan, Zhongyi Hu, Jiao Yuan, Jingjiang Pi, Yueying Wang, Lingling Fan, Zhaoqing Tang, Chunsheng Li, Xiaowen Hu, Janos L Tanyi, Yi Fan, Qihong Huang, Kathleen Montone, Chi V Dang, Lin Zhang
Strategies to enhance response to poly(adenosine diphosphate-ribose) polymerase inhibitor (PARPi) in primary and acquired homologous recombination (HR)-proficient tumors would be a major advance in cancer care. We used a drug synergy screen that combined a PARPi, olaparib, with 20 well-characterized epigenetic drugs and identified bromodomain and extraterminal domain inhibitors (BETis; JQ1, I-BET762, and OTX015) as drugs that acted synergistically with olaparib in HR-proficient cancer cells. Functional assays demonstrated that repressed BET activity reduces HR and thus enhances PARPi-induced DNA damage in cancer cells...
July 26, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28740608/gne-886-a-potent-and-selective-inhibitor-of-the-cat-eye-syndrome-chromosome-region-candidate-2-bromodomain-cecr2
#20
Terry D Crawford, James E Audia, Steve Bellon, Daniel J Burdick, Archana Bommi-Reddy, Alexandre Côté, Richard T Cummings, Martin Duplessis, E Megan Flynn, Michael Hewitt, Hon-Ren Huang, Hariharan Jayaram, Ying Jiang, Shivangi Joshi, James R Kiefer, Jeremy Murray, Christopher G Nasveschuk, Arianne Neiss, Eneida Pardo, F Anthony Romero, Peter Sandy, Robert J Sims, Yong Tang, Alexander M Taylor, Vickie Tsui, Jian Wang, Shumei Wang, Yongyun Wang, Zhaowu Xu, Laura Zawadzke, Xiaoqin Zhu, Brian K Albrecht, Steven R Magnuson, Andrea G Cochran
The biological function of bromodomains, epigenetic readers of acetylated lysine residues, remains largely unknown. Herein we report our efforts to discover a potent and selective inhibitor of the bromodomain of cat eye syndrome chromosome region candidate 2 (CECR2). Screening of our internal medicinal chemistry collection led to the identification of a pyrrolopyridone chemical lead, and subsequent structure-based drug design led to a potent and selective CECR2 bromodomain inhibitor (GNE-886) suitable for use as an in vitro tool compound...
July 13, 2017: ACS Medicinal Chemistry Letters
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