keyword
MENU ▼
Read by QxMD icon Read
search

Cancer AND BRD4

keyword
https://www.readbyqxmd.com/read/28930680/systematic-kinase-inhibitor-profiling-identifies-cdk9-as-a-synthetic-lethal-target-in-nut-midline-carcinoma
#1
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
#2
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
#3
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/28881673/bromodomain-inhibition-shows-antitumoral-activity-in-mice-and-human-luminal-breast-cancer
#4
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
#5
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/28854735/brd4-inhibitors-block-telomere-elongation
#6
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/28846832/induction-of-a-novel-isoform-of-the-lncrna-hotair-in-claudin-low-breast-cancer-cells-attached-to-extracellular-matrix
#7
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/28805822/intrinsic-bet-inhibitor-resistance-in-spop-mutated-prostate-cancer-is-mediated-by-bet-protein-stabilization-and-akt-mtorc1-activation
#8
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...
September 2017: Nature Medicine
https://www.readbyqxmd.com/read/28805821/opposing-effects-of-cancer-type-specific-spop-mutants-on-bet-protein-degradation-and-sensitivity-to-bet-inhibitors
#9
Hana Janouskova, Geniver El Tekle, Elisa Bellini, Namrata D Udeshi, Anna Rinaldi, Anna Ulbricht, Tiziano Bernasocchi, Gianluca Civenni, Marco Losa, Tanya Svinkina, Craig M Bielski, Gregory V Kryukov, Luciano Cascione, Sara Napoli, Radoslav I Enchev, David G Mutch, Michael E Carney, Andrew Berchuck, Boris J N Winterhoff, Russell R Broaddus, Peter Schraml, Holger Moch, Francesco Bertoni, Carlo V Catapano, Matthias Peter, Steven A Carr, Levi A Garraway, Peter J Wild, Jean-Philippe P Theurillat
It is generally assumed that recurrent mutations within a given cancer driver gene elicit similar drug responses. Cancer genome studies have identified recurrent but divergent missense mutations affecting the substrate-recognition domain of the ubiquitin ligase adaptor SPOP in endometrial and prostate cancers. The therapeutic implications of these mutations remain incompletely understood. Here we analyzed changes in the ubiquitin landscape induced by endometrial cancer-associated SPOP mutations and identified BRD2, BRD3 and BRD4 proteins (BETs) as SPOP-CUL3 substrates that are preferentially degraded by endometrial cancer-associated SPOP mutants...
September 2017: Nature Medicine
https://www.readbyqxmd.com/read/28805820/prostate-cancer-associated-spop-mutations-confer-resistance-to-bet-inhibitors-through-stabilization-of-brd4
#10
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...
September 2017: Nature Medicine
https://www.readbyqxmd.com/read/28781807/amplification-of-the-nsd3-brd4-chd8-pathway-in-pelvic-high-grade-serous-carcinomas-of-tubo-ovarian-and-endometrial-origin
#11
Derek H Jones, Douglas I Lin
Identification of novel therapeutics in pelvic high-grade serous carcinoma (HGSC) has been hampered by a paucity of actionable point mutations in target genes. The aim of the present study was to investigate the extent of amplification of the therapeutically targetable NSD3-CHD8-BRD4 pathway in pelvic HGSC, and to determine whether amplification is associated with worse prognosis. The Cancer Genome Atlas (TCGA) ovarian and endometrial cancer cohorts were retrospectively analyzed via online data-mining tools to test the association of NSD3, CHD8 and BRD4 genomic alterations with survival of pelvic HGSC patients...
August 2017: Molecular and Clinical Oncology
https://www.readbyqxmd.com/read/28771339/specific-acetylation-patterns-of-h2a-z-form-transient-interactions-with-the-bptf-bromodomain
#12
Gabriella T Perell, Neeraj K Mishra, Babu Sudhamalla, Peter D Ycas, Kabirul Islam, William C K Pomerantz
Post-translational lysine acetylation of histone tails affects both chromatin accessibility and recruitment of multifunctional bromodomain-containing proteins for modulating transcription. The bromodomain- and PHD finger-containing transcription factor (BPTF) regulates transcription but has also been implicated in 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 its affinity for BPTF with a specific recognition pattern of acetylated lysine residues of the N-terminal tail region...
September 5, 2017: Biochemistry
https://www.readbyqxmd.com/read/28766687/downregulation-of-brd4-inhibits-gallbladder-cancer-proliferation-and-metastasis-and-induces-apoptosis-via-pi3k-akt-pathway
#13
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/28747513/repression-of-bet-activity-sensitizes-homologous-recombination-proficient-cancers-to-parp-inhibition
#14
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/28729764/deciphering-the-role-of-micrornas-in-brd4-nut-fusion-gene-induced-nut-midline-carcinoma
#15
Ekta Pathak, Bhavya, Divya Mishra, Neelam Atri, Rajeev Mishra
NUT midline carcinoma (NMC) is a very aggressive and lethal type of squamous epithelial cell cancer caused due to fusion of BRD4 and NUT genes. The gene fusion results into a new fusion protein that promotes oncogenesis. The detailed molecular mechanisms underlying the NMC are still not clear and new findings are urgently required to complement the current efforts. Abnormal microRNAs (miRNA) expression promotes tumour formation by modulating the functional expression of critical genes other than the parent genes involved in tumour cell proliferation or survival...
2017: Bioinformation
https://www.readbyqxmd.com/read/28694331/transcriptional-elongation-control-of-hepatitis-b-virus-covalently-closed-circular-dna-transcription-by-super-elongation-complex-and-brd4
#16
Joel Celio Francisco, Qian Dai, Zhuojuan Luo, Yan Wang, Roxanne Hui-Heng Chong, Yee Joo Tan, Wei Xie, Guan-Huei Lee, Chengqi Lin
Chronic hepatitis B virus (HBV) infection can lead to liver cirrhosis and hepatocellular carcinoma. HBV reactivation during or after chemotherapy is a potentially fatal complication for cancer patients with chronic HBV infection. Transcription of HBV is a critical intermediate step of the HBV life cycle. However, factors controlling HBV transcription remain largely unknown. Here, we found that different P-TEFb complexes are involved in the transcription of the HBV viral genome. Both BRD4 and the super elongation complex (SEC) bind to the HBV genome...
October 1, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28681984/brd4-promotes-gastric-cancer-progression-through-the-transcriptional-and-epigenetic-regulation-of-c-myc
#17
Mingchen Ba, Hui Long, Zhaofei Yan, Shuai Wang, Yinbing Wu, Yinuo Tu, Yuanfeng Gong, Shuzhong Cui
Although the significance of BRD4 in the epigenetic memory and cancer genesis has been intensively investigated, little is known about its function and potential roles during the generation and progression of gastric cancer. We report here that BRD4 increases the proliferation and represses the apoptosis of gastric cancer cells through activating c-MYC via transcriptional and epigenetic regulation mechanisms. Expression analyses in both small and large cohort of sample show that BRD4 is highly expressed in gastric cancer tissues/cells when compared with the adjacent non-tumor tissues/normal cells...
July 6, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28673542/bet-bromodomain-proteins-function-as-master-transcription-elongation-factors-independent-of-cdk9-recruitment
#18
Georg E Winter, Andreas Mayer, Dennis L Buckley, Michael A Erb, Justine E Roderick, Sarah Vittori, Jaime M Reyes, Julia di Iulio, Amanda Souza, Christopher J Ott, Justin M Roberts, Rhamy Zeid, Thomas G Scott, Joshiawa Paulk, Kate Lachance, Calla M Olson, Shiva Dastjerdi, Sophie Bauer, Charles Y Lin, Nathanael S Gray, Michelle A Kelliher, L Stirling Churchman, James E Bradner
Processive elongation of RNA Polymerase II from a proximal promoter paused state is a rate-limiting event in human gene control. A small number of regulatory factors influence transcription elongation on a global scale. Prior research using small-molecule BET bromodomain inhibitors, such as JQ1, linked BRD4 to context-specific elongation at a limited number of genes associated with massive enhancer regions. Here, the mechanistic characterization of an optimized chemical degrader of BET bromodomain proteins, dBET6, led to the unexpected identification of BET proteins as master regulators of global transcription elongation...
July 6, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28636389/tumor-microenvironment-responsive-multistaged-nanoplatform-for-systemic-rnai-and-cancer-therapy
#19
Xiaoding Xu, Phei Er Saw, Wei Tao, Yujing Li, Xiaoyuan Ji, Mikyung Yu, Morteza Mahmoudi, Jonathan Rasmussen, Dana Ayyash, Yuxiao Zhou, Omid C Farokhzad, Jinjun Shi
While RNA interference (RNAi) therapy has demonstrated significant potential for cancer treatment, the effective and safe systemic delivery of RNAi agents such as small interfering RNA (siRNA) into tumor cells in vivo remains challenging. We herein reported a unique multistaged siRNA delivery nanoparticle (NP) platform, which is comprised of (i) a polyethylene glycol (PEG) surface shell, (ii) a sharp tumor microenvironment (TME) pH-responsive polymer that forms the NP core, and (iii) charge-mediated complexes of siRNA and tumor cell-targeting- and penetrating-peptide-amphiphile (TCPA) that are encapsulated in the NP core...
July 12, 2017: Nano Letters
https://www.readbyqxmd.com/read/28636361/machine-learning-assisted-approach-for-discovering-novel-inhibitors-targeting-bromodomain-containing-protein-4
#20
Jing Xing, Wenchao Lu, Rongfeng Liu, Yulan Wang, Yiqian Xie, Hao Zhang, Zhe Shi, Hao Jiang, Yu-Chih Liu, Kaixian Chen, Hualiang Jiang, Cheng Luo, Mingyue Zheng
Bromodomain-containing protein 4 (BRD4) is implicated in the pathogenesis of a number of different cancers, inflammatory diseases and heart failure. Much effort has been dedicated toward discovering novel scaffold BRD4 inhibitors (BRD4is) with different selectivity profiles and potential antiresistance properties. Structure-based drug design (SBDD) and virtual screening (VS) are the most frequently used approaches. Here, we demonstrate a novel, structure-based VS approach that uses machine-learning algorithms trained on the priori structure and activity knowledge to predict the likelihood that a compound is a BRD4i based on its binding pattern with BRD4...
July 24, 2017: Journal of Chemical Information and Modeling
keyword
keyword
90154
1
2
Fetch more papers »
Fetching more papers... Fetching...
Read by QxMD. Sign in or create an account to discover new knowledge that matter to you.
Remove bar
Read by QxMD icon Read
×

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"