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https://www.readbyqxmd.com/read/28446540/human-prostate-luminal-cell-differentiation-requires-notch3-induction-by-p38-mapk-and-myc
#1
Sander B Frank, Penny L Berger, Mats Ljungman, Cindy K Miranti
Many pathways dysregulated in prostate cancer are also involved in epithelial differentiation. To better understand prostate tumor initiation, we sought to investigate specific genes and mechanisms required for normal basal to luminal cell differentiation. Utilizing human prostate basal epithelial cells and an in vitro differentiation model, we tested the hypothesis that p38-MAPK regulation of NOTCH3, via MYC, is required for luminal differentiation. Inhibition (SB202190, BIRB796) or knockdown of p38α and/or p38δ prevented proper differentiation...
April 26, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/28418907/bh3-mimetics-and-bet-inhibitors-elicit-enhanced-lethality-in-malignant-glioma
#2
Chiaki Tsuge Ishida, Elena Bianchetti, Chang Shu, Marc-Eric Halatsch, Mike-Andrew Westhoff, Georg Karpel-Massler, Markus D Siegelin
Drug combination therapies remain pivotal for the treatment of heterogeneous malignancies, such as glioblastomas. Here, we show a novel lethal interaction between Bcl-xL and c-myc inhibition accomplished by bromodomain protein inhibitors. Established, patient-derived xenograft and stem cell-like glioma cells were treated with the novel bromodomain protein inhibitors, JQ1 and OTX015, along with BH3-mimetics, ABT263 or Obatoclax. Synergy was assessed by calculation of CI values. Small interfering RNAs (siRNAs) were used for gene silencing and mechanistic studies...
March 18, 2017: Oncotarget
https://www.readbyqxmd.com/read/28417956/establishment-and-characterization-of-an-orthotopic-patient-derived-group-3-medulloblastoma-model-for-preclinical-drug-evaluation
#3
Emma Sandén, Cecilia Dyberg, Cecilia Krona, Gabriel Gallo-Oller, Thale Kristin Olsen, Julio Enríquez Pérez, Malin Wickström, Atosa Estekizadeh, Marcel Kool, Edward Visse, Tomas J Ekström, Peter Siesjö, John Inge Johnsen, Anna Darabi
Medulloblastomas comprise a heterogeneous group of tumours and can be subdivided into four molecular subgroups (WNT, SHH, Group 3 and Group 4) with distinct prognosis, biological behaviour and implications for targeted therapies. Few experimental models exist of the aggressive and poorly characterized Group 3 tumours. In order to establish a reproducible transplantable Group 3 medulloblastoma model for preclinical therapeutic studies, we acquired a patient-derived tumour sphere culture and inoculated low-passage spheres into the cerebellums of NOD-scid mice...
April 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28415755/mitochondrial-matrix-chaperone-and-c-myc-inhibition-causes-enhanced-lethality-in-glioblastoma
#4
Chiaki Tsuge Ishida, Chang Shu, Marc-Eric Halatsch, Mike-Andrew Westhoff, Dario C Altieri, Georg Karpel-Massler, Markus David Siegelin
Malignant gliomas display high levels of the transcription factor c-myc and organize a tumor specific chaperone network within mitochondria. Here, we show that c-myc along with mitochondrial chaperone inhibition displays massive tumor cell death. Inhibition of mitochondrial matrix chaperones and c-myc was established by utilizing genetic as well as pharmacological approaches. Bromodomain and extraterminal (BET) family protein inhibitors, JQ1 and OTX015, were used for c-myc inhibition. Gamitrinib was applied to interfere with mitochondrial matrix chaperones...
March 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28408401/synergistic-immunostimulatory-effects-and-therapeutic-benefit-of-combined-histone-deacetylase-and-bromodomain-inhibition-in-non-small-cell-lung-cancer
#5
Dennis Adeegbe, Yan Liu, Patrick H Lizotte, Yusuke Kamihara, Amir R Aref, Christina Almonte, Ruben Dries, Yuyang Li, Shengwu Liu, Xiaoen Wang, Tiquella Warner-Hatten, Jessica Castrillon, Guo-Cheng Yuan, Neermala Poudel-Neupane, Haikuo Zhang, Jennifer L Guerriero, Shiwei Han, Mark M Awad, David A Barbie, Jerome Ritz, Simon S Jones, Peter S Hammerman, James E Bradner, Steven N Quayle, Kwok-Kin Wong
Effective therapies for non-small cell lung cancer (NSCLC) remain challenging despite an increasingly comprehensive understanding of somatically altered oncogenic pathways. It is now clear that therapeutic agents with potential to impact the tumor immune microenvironment potentiate immune-orchestrated therapeutic benefit. Herein we evaluated the immunoregulatory properties of histone deacetylase (HDAC) and bromodomain inhibitors, two classes of drugs that modulate the epigenome, with a focus on key cell subsets that are engaged in an immune response...
April 13, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28391274/inhibition-of-brd4-suppresses-cell-proliferation-and-induces-apoptosis-in-renal-cell-carcinoma
#6
Xinchao Wu, Dong Liu, Xuemei Gao, Fei Xie, Dan Tao, Xingyuan Xiao, Liang Wang, Guosong Jiang, Fuqing Zeng
BACKGROUND/AIMS: Renal cell carcinoma (RCC) remains an intractable genitourinary malignancy. Resistance to chemotherapy or targeted therapies in RCC is presumably due to the complicated underlying molecular mechanisms and insufficient understanding. The aim of this research was to assess the expression and role of bromodomain-4 protein (BRD4) in RCC and evaluate the effects of BRD4 inhibitor JQ1 for RCC treatment. METHODS: BRD4 expressionlevels were assessed by qRT-PCR and western blot in RCC tissues and cells...
April 7, 2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/28368473/targeting-myc-as-a-therapeutic-intervention-for-anaplastic-thyroid-cancer
#7
Keisuke Enomoto, Xuguang Zhu, Sunmi Park, Li Zhao, Yuelin J Zhu, Mark C Willingham, Jun Qi, John A Copland, Paul Meltzer, Sheue-Yann Cheng
Context: Recent studies showed that transcription of the MYC gene is driven by interaction of bromodomain and extraterminal domain (BET) proteins with acetylated histones on chromatin. A potent inhibitor, JQ1, which effectively disrupts the interaction of BET proteins with acetylated histones, preferentially suppresses transcription of the MYC gene. We recently reported that JQ1 decreased thyroid tumor growth and improved survival in a mouse model of anaplastic thyroid cancer (ATC) by targeting MYC transcription...
March 28, 2017: Journal of Clinical Endocrinology and Metabolism
https://www.readbyqxmd.com/read/28356707/epigenetic-intervention-with-a-bet-inhibitor-ameliorates-acute-retinal-ganglion-cell-death-in-mice
#8
Jun Li, Lei Zhao, Go Urabe, Yingmei Fu, Lian-Wang Guo
PURPOSE: The bromo and extraterminal (BET) epigenetic "reader" family is becoming an appealing new therapeutic target for several common diseases, yet little is known of its role in retinal neurodegeneration. We explored the potential of BET inhibition in the protection of retinal ganglion cells (RGCs). METHODS: To test the therapeutic effect of JQ1, an inhibitor highly selective for the BET family of proteins, we used an acute RGC damage model induced by N-methyl-D-aspartic acid (NMDA) excitotoxicity...
2017: Molecular Vision
https://www.readbyqxmd.com/read/28336808/potent-dual-bet-bromodomain-kinase-inhibitors-as-value-added-multi-targeted-chemical-probes-and-cancer-therapeutics
#9
Stuart W Ember, Que T Lambert, Norbert Berndt, Steven Gunawan, Muhammad Ayaz, Marilena Tauro, Jin-Yi Zhu, Paula J Cranfill, Patricia Greninger, Conor C Lynch, Cyril H Benes, Harshani R Lawrence, Gary W Reuther, Nicholas J Lawrence, Ernst Schonbrunn
Synergistic action of kinase and BET bromodomain inhibitors in cell killing has been reported for a variety of cancers. Using the chemical scaffold of the JAK2 inhibitor TG101348 we developed and characterized single agents which potently and simultaneously inhibit BRD4 and a specific set of oncogenic tyrosine kinases including JAK2, FLT3, RET, and ROS1. Lead compounds showed on-target inhibition in several blood cancer cell lines and were highly efficacious at inhibiting the growth of hematopoietic progenitor cells from myeloproliferative neoplasm (MPN) patients...
March 23, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28322577/bet-proteins-are-a-key-component-of-immunoglobulin-gene-expression
#10
Jung Min Shim, Jin S Lee, Kirsty E Russell, Coen H Wiegman, Peter J Barnes, David Fear, Ian M Adcock, Andrew L Durham
AIM: BET proteins have been shown to regulate gene expression including inflammatory genes. METHODS: In order to investigate the role of the BET proteins in immunoglobulin production we treated the human B-cell line CLNH11.4 and primary human B cells and ozone-exposed mice with BET inhibitors (JQ1 or IBET151). RESULTS: Both proliferation and IgG production were reduced by JQ1 in a concentration-dependent manner. JQ1 significantly reduced immunoglobulin gene transcription...
March 21, 2017: Epigenomics
https://www.readbyqxmd.com/read/28292938/combinatorial-screening-of-pancreatic-adenocarcinoma-reveals-sensitivity-to-drug-combinations-including-bromodomain-inhibitor-plus-neddylation-inhibitor
#11
Casey G Langdon, James T Platt, Robert E Means, Pinar Iyidogan, Ramanaiah Mamillapalli, Michael Klein, Matthew A Held, Jong Woo Lee, Ja Seok Koo, Christos Hatzis, Howard S Hochster, David F Stern
Pancreatic adenocarcinoma (PDAC) is the fourth most common cause of cancer death in the United States. PDAC is difficult to manage effectively, with a five-year survival rate of only 5%. PDAC is largely driven by activating KRAS mutations, and as such, cannot be directly targeted with therapeutic agents that affect the activated protein. Instead, inhibition of downstream signaling and other targets will be necessary to effectively manage PDAC. Here, we describe a tiered single-agent and combination compound screen to identify targeted agents that impair growth of a panel of PDAC cell lines...
March 14, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28286180/dysregulation-of-bet-proteins-in-levodopa-induced-dyskinesia
#12
David A Figge, David G Standaert
Levodopa (L-DOPA) remains the most effective pharmacological treatment for Parkinson Disease (PD) but its use is limited by the development of debilitating drug-related side effects, particularly L-DOPA induced dyskinesia (LID). LID is a consequence of long-term L-DOPA use, and in model systems is characterized by a "priming effect", whereby initial administrations of L-DOPA trigger a sensitized biochemical and transcriptional response upon subsequent dopaminergic stimulation. Preliminary studies into the mechanisms underlying this cellular memory have indicated an important role for epigenetic change but many of the downstream mechanisms remain unknown...
June 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28283057/super-enhancer-mediated-rna-processing-revealed-by-integrative-microrna-network-analysis
#13
Hiroshi I Suzuki, Richard A Young, Phillip A Sharp
Super-enhancers are an emerging subclass of regulatory regions controlling cell identity and disease genes. However, their biological function and impact on miRNA networks are unclear. Here, we report that super-enhancers drive the biogenesis of master miRNAs crucial for cell identity by enhancing both transcription and Drosha/DGCR8-mediated primary miRNA (pri-miRNA) processing. Super-enhancers, together with broad H3K4me3 domains, shape a tissue-specific and evolutionarily conserved atlas of miRNA expression and function...
March 9, 2017: Cell
https://www.readbyqxmd.com/read/28275007/gene-expression-profiling-of-patient-derived-pancreatic-cancer-xenografts-predicts-sensitivity-to-the-bet-bromodomain-inhibitor-jq1-implications-for-individualized-medicine-efforts
#14
Benjamin Bian, Martin Bigonnet, Odile Gayet, Celine Loncle, Aurélie Maignan, Marine Gilabert, Vincent Moutardier, Stephane Garcia, Olivier Turrini, Jean-Robert Delpero, Marc Giovannini, Philippe Grandval, Mohamed Gasmi, Mehdi Ouaissi, Veronique Secq, Flora Poizat, Rémy Nicolle, Yuna Blum, Laetitia Marisa, Marion Rubis, Jean-Luc Raoul, James E Bradner, Jun Qi, Gwen Lomberk, Raul Urrutia, Andres Saul, Nelson Dusetti, Juan Iovanna
c-MYC controls more than 15% of genes responsible for proliferation, differentiation, and cellular metabolism in pancreatic as well as other cancers making this transcription factor a prime target for treating patients. The transcriptome of 55 patient-derived xenografts show that 30% of them share an exacerbated expression profile of MYC transcriptional targets (MYC-high). This cohort is characterized by a high level of Ki67 staining, a lower differentiation state, and a shorter survival time compared to the MYC-low subgroup...
April 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28270499/pd-l1-is-a-therapeutic-target-of-the-bromodomain-inhibitor-jq1-and-combined-with-hla-class-i-a-promising-prognostic-biomarker-in-neuroblastoma
#15
Ombretta Melaiu, Marco Mina, Marco Chierici, Renata Boldrini, Giuseppe Jurman, Paolo Romania, Valerio D'Alicandro, Maria Chiara Benedetti, Aurora Castellano, Tao Liu, Cesare Furlanello, Franco Locatelli, Doriana Fruci
PURPOSE: This study sought to evaluate expression of PD-L1 and HLA class I on neuroblastoma cells and PD-1 and LAG3 on tumor-infiltrating lymphocytes to better define patient risk-stratification and understand whether this tumor may benefit from therapies targeting immune-checkpoint molecules. EXPERIMENTAL DESIGN: In situ immunohistochemical staining for PD-L1, HLA class I, PD-1 and LAG3 was assessed in 77 neuroblastoma specimens, previously characterized for tumor-infiltrating T cell-density, and correlated with clinical outcome...
March 7, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28265070/bet-n-terminal-bromodomain-inhibition-selectively-blocks-th17-cell-differentiation-and-ameliorates-colitis-in-mice
#16
Kalung Cheung, Geming Lu, Rajal Sharma, Adam Vincek, Ruihua Zhang, Alexander N Plotnikov, Fan Zhang, Qiang Zhang, Ying Ju, Yuan Hu, Li Zhao, Xinye Han, Jamel Meslamani, Feihong Xu, Anbalagan Jaganathan, Tong Shen, Hongfa Zhu, Elena Rusinova, Lei Zeng, Jiachi Zhou, Jianjun Yang, Liang Peng, Michael Ohlmeyer, Martin J Walsh, David Y Zhang, Huabao Xiong, Ming-Ming Zhou
T-helper 17 (Th17) cells have important functions in adaptor immunity and have also been implicated in inflammatory disorders. The bromodomain and extraterminal domain (BET) family proteins regulate gene transcription during lineage-specific differentiation of naïve CD4(+) T cells to produce mature T-helper cells. Inhibition of acetyl-lysine binding of the BET proteins by pan-BET bromodomain (BrD) inhibitors, such as JQ1, broadly affects differentiation of Th17, Th1, and Th2 cells that have distinct immune functions, thus limiting their therapeutic potential...
March 14, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28254412/bromodomain-inhibitors-jq1-and-i-bet-762-as-potential-therapies-for-pancreatic-cancer
#17
Ana S Leal, Charlotte R Williams, Darlene B Royce, Patricia A Pioli, Michael B Sporn, Karen T Liby
Bromodomain inhibitors (JQ1 and I-BET 762) are a new generation of selective, small molecule inhibitors that target BET (bromodomain and extra terminal) proteins. By impairing their ability to bind to acetylated lysines on histones, bromodomain inhibitors interfere with transcriptional initiation and elongation. BET proteins regulate several genes responsible for cell cycle, apoptosis and inflammation. In this study, JQ1 and I-BET 762 decreased c-Myc and p-Erk 1/2 protein levels and inhibited proliferation in pancreatic cancer cells...
February 27, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28249162/bet-bromodomain-inhibitors-engage-the-host-immune-system-and-regulate-expression-of-the-immune-checkpoint-ligand-pd-l1
#18
Simon J Hogg, Stephin J Vervoort, Sumit Deswal, Christopher J Ott, Jason Li, Leonie A Cluse, Paul A Beavis, Phillip K Darcy, Benjamin P Martin, Andrew Spencer, Anna K Traunbauer, Irina Sadovnik, Karin Bauer, Peter Valent, James E Bradner, Johannes Zuber, Jake Shortt, Ricky W Johnstone
BET inhibitors (BETi) target bromodomain-containing proteins and are currently being evaluated as anti-cancer agents. We find that maximal therapeutic effects of BETi in a Myc-driven B cell lymphoma model required an intact host immune system. Genome-wide analysis of the BETi-induced transcriptional response identified the immune checkpoint ligand Cd274 (Pd-l1) as a Myc-independent, BETi target-gene. BETi directly repressed constitutively expressed and interferon-gamma (IFN-γ) induced CD274 expression across different human and mouse tumor cell lines and primary patient samples...
February 28, 2017: Cell Reports
https://www.readbyqxmd.com/read/28248992/altered-regulation-and-expression-of-genes-by-bet-family-of-proteins-in-copd-patients
#19
Rajneesh Malhotra, Nisha Kurian, Xiao-Hong Zhou, Fanyi Jiang, Susan Monkley, Amy DeMicco, Ib G Clausen, Göran Delgren, Goran Edenro, Miika J Ahdesmäki, Maryam Clausen, Lisa Öberg, Elisabeth Israelsson, Graham Belfield, Outi Vaarala
BACKGROUND: BET proteins (BRD2, BRD3, BRDT and BRD4) belong to the family of bromodomain containing proteins, which form a class of transcriptional co-regulators. BET proteins bind to acetylated lysine residues in the histones of nucleosomal chromatin and function either as co-activators or co-repressors of gene expression. An imbalance between HAT and HDAC activities resulting in hyperacetylation of histones has been identified in COPD. We hypothesized that pan-BET inhibitor (JQ1) treatment of BET protein interactions with hyperacetylated sites in the chromatin will regulate excessive activation of pro-inflammatory genes in key inflammatory drivers of alveolar macrophages (AM) in COPD...
2017: PloS One
https://www.readbyqxmd.com/read/28143717/the-bet-bromodomain-inhibitor-jq1-radiosensitizes-non-small-cell-lung-cancer-cells-by-upregulating-p21
#20
Jian Wang, Ye Wang, Hong Mei, Zhongyuan Yin, Yuanyuan Geng, Tao Zhang, Gang Wu, Zhenyu Lin
Radiotherapy is an important treatment modality in the management of locally advanced non-small cell lung cancer (NSCLC). However, radioresistance markedly impairs its efficacy in clinic. Bromodomain and extra-terminal (BET) bromodomain inhibitors have demonstrated dramatic antitumor activity in several preclinical human cancer models. In this study, we investigated for the first time the effect of JQ1, a novel BET bromodomain inhibitor, on tumor cell radiosensitivity of NSCLC in vitro and in vivo. Our results demonstrated that JQ1 significantly enhanced the effect of irradiation in NSCLC cell lines through a c-myc-independent mechanism...
April 10, 2017: Cancer Letters
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