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https://www.readbyqxmd.com/read/29142067/jq1-induces-dna-damage-and-apoptosis-and-inhibits-tumor-growth-in-a-patient-derived-xenograft-model-of-cholangiocarcinoma
#1
Patrick L Garcia, Aubrey L Miller, Tracy L Gamblin, Leona N Council, John D Christein, J Pablo Arnoletti, Marty J Heslin, Sushanth Reddy, Joseph H Richardson, Xiangqin Cui, Robert C A M van Waardenburg, James E Bradner, Eddy S Yang, Karina J Yoon
Cholangiocarcinoma (CCA) is a fatal disease with a five-year survival of <30%. For a majority of patients chemotherapy is the only therapeutic option, and virtually all patients relapse. Gemcitabine is the frontline agent for treatment of CCA. Patients treated with gemcitabine monotherapy survive ~8 months. Combining this agent with cisplatin increases survival by ~3 months, but neither regimen produces durable remissions. The molecular etiology of this disease is poorly understood. To facilitate molecular characterization and development of effective therapies for CCA, we established a panel of patient-derived xenograft (PDX) models of CCA...
November 15, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29139214/a-theoretical-insight-into-selectivity-of-inhibitors-toward-two-domains-of-bromodomain-containing-protein-4-using-molecular-dynamics-simulations
#2
Jing Su, Xinguo Liu, Shaolong Zhang, Fangfang Yan, Qinggang Zhang, Jianzhong Chen
Bromodomains (BRDs) have been an attractive candidate for development of efficient inhibitors toward gene transcription. Molecular dynamics (MD) simulations followed by principal component (PC) analysis were performed to investigate binding selectivity of inhibitors RVX297, BSP, JQ1, SF2523 and CPD2 toward two domains (BD1 and BD2) of bromodomain-containing protein 4 (BRD4). The results show that inhibitor bindings exert different effect on motions of the BC-loops in BD1 and BD2. The rank of binding free energies calculated by using molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method agrees with the one determined by experiment...
November 15, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/29133788/regulation-of-angiotensin-ii-actions-by-enhancers-and-super-enhancers-in-vascular-smooth-muscle-cells
#3
Sadhan Das, Parijat Senapati, Zhuo Chen, Marpadga A Reddy, Rituparna Ganguly, Linda Lanting, Varun Mandi, Anita Bansal, Amy Leung, Selena Zhang, Ye Jia, Xiwei Wu, Dustin E Schones, Rama Natarajan
Angiotensin II (AngII) promotes hypertension and atherosclerosis by activating growth-promoting and pro-inflammatory gene expression in vascular smooth muscle cells (VSMCs). Enhancers and super-enhancers (SEs) play critical roles in driving disease-associated gene expression. However, enhancers/SEs mediating VSMC dysfunction remain uncharacterized. Here, we show that AngII alters vascular enhancer and SE repertoires in cultured VSMCs in vitro, ex vivo, and in AngII-infused mice aortas in vivo. AngII-induced enhancers/SEs are enriched in binding sites for signal-dependent transcription factors and dependent on key signaling kinases...
November 13, 2017: Nature Communications
https://www.readbyqxmd.com/read/29113796/the-bet-brd-inhibitor-jq1-attenuates-diabetes-induced-cognitive-impairment-in-rats-by-targeting-nox4-nrf2-redox-imbalance
#4
Ershun Liang, Min Ma, Lei Wang, Xue Liu, Jinfeng Xu, Mingxiang Zhang, Ruixue Yang, Yuxia Zhao
Diabetes-induced oxidative damage is believed to play an important role in the development of cognitive dysfunction. In this study, the involvement of the Nox4-Nrf2 redox imbalance was investigated. STZ-induced diabetic rats exhibited obvious oxidative stress and apoptosis in the hippocampus assessed by augmentation of lipid peroxidation, positive TUNEL staining, elevated ratio of Bax/Bcl-2 and increased caspase 3 activity. Furthermore, hyperglycemia markedly increased Nox4 activity and reduced the activation of Nrf2 by suppressing its up-stream regulatory Akt as well as down-stream target HO-1...
November 4, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29082287/flow-cytometric-analysis-of-hiv-1-transcriptional-activity-in-response-to-shrna-knockdown-in-a2-and-a72-j-lat-cell-lines
#5
Daniela Boehm, Melanie Ott
The main obstacle to eradicating HIV-1 from patients is post-integration latency (Finzi et al., 1999). Antiretroviral treatments target only actively replicating virus, while latent infections that have low or no transcriptional activity remain untreated (Sedaghat et al., 2007). To eliminate viral reservoirs, one strategy focuses on reversing HIV-1 latency via 'shock and kill' (Deeks, 2012). The basis of this strategy is to overcome the molecular mechanisms of HIV-1 latency by therapeutically inducing viral gene and protein expression under antiretroviral therapy and to cause selective cell death via the lytic properties of the virus, or the immune system now recognizing the infected cells...
June 5, 2017: Bio-protocol
https://www.readbyqxmd.com/read/29074567/image-based-drug-screen-identifies-hdac-inhibitors-as-novel-golgi-disruptors-synergizing-with-jq1
#6
Mathieu Gendarme, Jan Baumann, Tatiana I Ignashkova, Ralph K Lindemann, Jan H Reiling
The Golgi apparatus is increasingly recognized as a major hub for cellular signaling and is involved in numerous pathologies, including neurodegenerative diseases and cancer. The study of Golgi stress-induced signaling pathways relies on the selectivity of the available tool compounds of which currently only a few are known. To discover novel Golgi-fragmenting agents, transcriptomic profiles of cells treated with brefeldin A, golgicide A or monensin were generated and compared to a database of gene expression profiles from cells treated with other bioactive small molecules...
October 26, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/29050985/bromodomain-protein-brd4-promotes-cell-proliferation-in-skin-squamous-cell-carcinoma
#7
Tie Xiang, Jin-Yu Bai, Chang She, Dao-Jiang Yu, Xiao-Zhong Zhou, Tian-Lan Zhao
The present study examined the expression and biological functions of bromodomain-containing protein 4 (BRD4) in skin squamous cell carcinoma (SCC) cells. Our results show that BRD4 mRNA and protein expression was upregulated in human skin SCC cells, as compared to its level in the normal skin keratinocytes and fibroblasts. Treatment with BRD4 inhibitors, JQ1 and CPI203, resulted in proliferation inhibition, apoptosis and cell cycle arrest in both established (A431 cell line) and primary skin SCC cells. Furthermore, BRD4 knockdown (by targeted shRNAs) or knockout (by CRISPR/Cas9) largely inhibited A431 cell proliferation...
October 16, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28972303/kinome-wide-transcriptional-profiling-of-uveal-melanoma-reveals-new-vulnerabilities-to-targeted-therapeutics
#8
Fiona P Bailey, Kim Clarke, Helen Kalirai, Jenna Kenyani, Haleh Shahidipour, Francesco Falciani, Judy M Coulson, Joseph J Sacco, Sarah E Coupland, Patrick A Eyers
Metastatic uveal melanoma (UM) is invariably fatal, usually within a year of diagnosis. There are currently no effective therapies, and clinical studies employing kinase inhibitors have so far demonstrated limited success. This is despite common activating mutations in GNAQ/11 genes, which trigger signalling pathways that might predispose tumours to a variety of targeted drugs. In this study, we have profiled kinome expression network dynamics in various human ocular melanomas. We uncovered a shared transcriptional profile in human primary UM samples and across a variety of experimental cell-based models...
October 3, 2017: Pigment Cell & Melanoma Research
https://www.readbyqxmd.com/read/28950657/the-bet-bromodomain-inhibitor-jq1-synergized-abt-263-against-colorectal-cancer-cells-through-suppressing-c-myc-induced-mir-1271-5p-expression
#9
Zhenqian Wu, Zedong Hu, Xiaodong Han, Zhongnan Li, Qingchao Zhu, Yu Wang, Qi Zheng, Jun Yan
Colorectal cancer (CRC) cells undergo apoptosis in the presence of the small-molecule inhibitor ABT-263 by up-regulating antiapoptotic Bcl-2 family members. However, the resistance to ABT-263 gradually developed in most solid tumors due to its low affinity to Mcl-1. Here, we found the BET-Bromodomain inhibitor JQ1, when combined with ABT-263, synergistically reduced Mcl-1 protein level, induced apoptosis, and decreased cell viability in the CRC HCT-15, HT-29 and SW620 cells. The subsequent mechanism study revealed that a pathway of c-Myc/miR-1271-5p/Noxa/Mcl-1 underlies the synergistic effect of such combination treatment...
November 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28949335/the-bet-brd-inhibitor-jq1-improves-brain-plasticity-in-wt-and-app-mice
#10
E Benito, B Ramachandran, H Schroeder, G Schmidt, H Urbanke, S Burkhardt, V Capece, C Dean, A Fischer
Histone acetylation is essential for memory formation and its deregulation contributes to the pathogenesis of Alzheimer's disease. Thus, targeting histone acetylation is discussed as a novel approach to treat dementia. The histone acetylation landscape is shaped by chromatin writer and eraser proteins, while readers link chromatin state to cellular function. Chromatin readers emerged novel drug targets in cancer research but little is known about the manipulation of readers in the adult brain. Here we tested the effect of JQ1-a small-molecule inhibitor of the chromatin readers BRD2, BRD3, BRD4 and BRDT-on brain function and show that JQ1 is able to enhance cognitive performance and long-term potentiation in wild-type animals and in a mouse model for Alzheimer's disease...
September 26, 2017: Translational Psychiatry
https://www.readbyqxmd.com/read/28931940/brd4-regulates-adiponectin-gene-induction-by-recruiting-the-p-tefb-complex-to-the-transcribed-region-of-the-gene
#11
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/28916223/bet-bromodomain-inhibitors-modulate-epigenetic-patterns-at-the-diacylglycerol-kinase-alpha-enhancer-associated-with-radiation-induced-fibrosis
#12
Gintvile Valinciute, Christoph Weigel, Marlon R Veldwijk, Christopher C Oakes, Carsten Herskind, Frederik Wenz, Christoph Plass, Peter Schmezer, Odilia Popanda
BACKGROUND AND PURPOSE: Fibrosis is a frequent adverse effect of radiotherapy and no effective treatments are currently available to prevent or reverse fibrotic disease. We have previously identified altered epigenetic patterns at a gene enhancer of the diacylglycerol kinase alpha (DGKA) locus in normal skin fibroblasts derived from fibrosis patients. An open chromatin pattern related to radiation-inducibility of DGKA is associated with onset of radiation-induced fibrosis. Here, we explore epigenetic modulation of DGKA as a way to mitigate predisposition to fibrosis...
September 12, 2017: Radiotherapy and Oncology: Journal of the European Society for Therapeutic Radiology and Oncology
https://www.readbyqxmd.com/read/28885069/jq1-reduces-epstein-barr-virus-associated-lymphoproliferative-disease-in-mice-without-sustained-oncogene-repression
#13
Amanda He, Jj L Miranda
No abstract text is available yet for this article.
September 8, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28881673/bromodomain-inhibition-shows-antitumoral-activity-in-mice-and-human-luminal-breast-cancer
#14
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
#15
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/28878233/a-chalcone-derivative-reactivates-latent-hiv-1-transcription-through-activating-p-tefb-and-promoting-tat-sec-interaction-on-viral-promoter
#16
Jun Wu, Ming-Tao Ao, Rui Shao, Hui-Ru Wang, Diao Yu, Mei-Juan Fang, Xiang Gao, Zhen Wu, Qiang Zhou, Yu-Hua Xue
The principal barrier to the eradication of HIV/AIDS is the existence of latent viral reservoirs. One strategy to overcome this barrier is to use latency-reversing agents (LRAs) to reactivate the latent proviruses, which can then be eliminated by effective anti-retroviral therapy. Although a number of LRAs have been found to reactivate latent HIV, they have not been used clinically due to high toxicity and poor efficacy. In this study, we report the identification of a chalcone analogue called Amt-87 that can significantly reactivate the transcription of latent HIV provirses and act synergistically with known LRAs such as prostratin and JQ1 to reverse latency...
September 6, 2017: Scientific Reports
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
#17
Yafei Jiang, Libo Zhu, Tao Zhang, Haiming Lu, Cong Wang, Bao Xue, Xun Xu, Yu Liu, Zhengdong Cai, Weilin Sang, Yingqi Hua, Jinzhong Ma
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/28835800/design-and-optimization-of-benzopiperazines-as-potent-inhibitors-of-bet-bromodomains
#18
David S Millan, Katherine J Kayser-Bricker, Matthew W Martin, Adam C Talbot, Shawn E R Schiller, Torsten Herbertz, Grace L Williams, George P Luke, Stephen Hubbs, Monica A Alvarez Morales, Daniel Cardillo, Paul Troccolo, Rachel L Mendes, Crystal McKinnon
A protein structure-guided drug design approach was employed to develop small molecule inhibitors of the BET family of bromodomains that were distinct from the known (+)-JQ1 scaffold class. These efforts led to the identification of a series of substituted benzopiperazines with structural features that enable interactions with many of the affinity-driving regions of the bromodomain binding site. Lipophilic efficiency was a guiding principle in improving binding affinity alongside drug-like physicochemical properties that are commensurate with oral bioavailability...
August 10, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28813519/expression-and-inhibition-of-brd4-ezh2-and-top2a-in-neurofibromas-and-malignant-peripheral-nerve-sheath-tumors
#19
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/28805820/prostate-cancer-associated-spop-mutations-confer-resistance-to-bet-inhibitors-through-stabilization-of-brd4
#20
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
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