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https://www.readbyqxmd.com/read/28096419/stromal-cues-regulate-the-pancreatic-cancer-epigenome-and-metabolome
#1
Mara H Sherman, Ruth T Yu, Tiffany W Tseng, Cristovao M Sousa, Sihao Liu, Morgan L Truitt, Nanhai He, Ning Ding, Christopher Liddle, Annette R Atkins, Mathias Leblanc, Eric A Collisson, John M Asara, Alec C Kimmelman, Michael Downes, Ronald M Evans
A fibroinflammatory stromal reaction cooperates with oncogenic signaling to influence pancreatic ductal adenocarcinoma (PDAC) initiation, progression, and therapeutic outcome, yet the mechanistic underpinning of this crosstalk remains poorly understood. Here we show that stromal cues elicit an adaptive response in the cancer cell including the rapid mobilization of a transcriptional network implicated in accelerated growth, along with anabolic changes of an altered metabolome. The close overlap of stroma-induced changes in vitro with those previously shown to be regulated by oncogenic Kras in vivo suggests that oncogenic Kras signaling-a hallmark and key driver of PDAC-is contingent on stromal inputs...
January 17, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28032455/in-silico-design-and-bioevaluation-of-selective-benzotriazepine-brd4-inhibitors-with-potent-antiosteoclastogenic-activity
#2
Vishwa Deepak, Binglin Wang, Dwayne Koot, Abe Kasonga, Xiao Xing Stander, Magdalena Coetzee, Andre Stander
The bromodomain (BRD) and extra-terminal domain (BET) protein family binds to acetylated histones on lysine residues and act as epigenetic readers. Recently, the role of this protein family in bone loss has been gaining attention. Earlier studies have reported that benzotriazepine (Bzt) derivatives could be effective inhibitors of BET proteins. In this study by using in silico tools we designed three Bzt analogs (W49, W51, and W52). By docking, molecular simulations and chemiluminescent alpha screen binding assay we show that the studied analogs were selective at inhibiting BRD4 when compared to BRD2...
December 29, 2016: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28008999/genetic-architecture-differences-between-pediatric-and-adult-onset-inflammatory-bowel-diseases-in-the-polish-population
#3
Jerzy Ostrowski, Agnieszka Paziewska, Izabella Lazowska, Filip Ambrozkiewicz, Krzysztof Goryca, Maria Kulecka, Tomasz Rawa, Jakub Karczmarski, Michalina Dabrowska, Natalia Zeber-Lubecka, Roman Tomecki, Anna Kluska, Aneta Balabas, Magdalena Piatkowska, Katarzyna Paczkowska, Jaroslaw Kierkus, Piotr Socha, Michal Lodyga, Grazyna Rydzewska, Maria Klopocka, Grazyna Mierzwa, Barbara Iwanczak, Elzbieta Krzesiek, Katarzyna Bak-Drabik, Jaroslaw Walkowiak, Beata Klincewicz, Piotr Radwan, Urszula Grzybowska-Chlebowczyk, Piotr Landowski, Agnieszka Jankowska, Bartosz Korczowski, Teresa Starzynska, Piotr Albrecht, Michal Mikula
Most inflammatory bowel diseases (IBDs) are classic complex disorders represented by common alleles. Here we aimed to define the genetic architecture of pediatric and adult-onset IBDs for the Polish population. A total of 1495 patients were recruited, including 761 patients with Crohn's disease (CD; 424 pediatric), 734 patients with ulcerative colitis (UC; 390 pediatric), and 934 healthy controls. Allelotyping employed a pooled-DNA genome-wide association study (GWAS) and was validated by individual genotyping...
December 23, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27997612/signatures-of-crested-ibis-mhc-revealed-by-recombination-screening-and-short-reads-assembly-strategy
#4
Liao Chang, Shiyang He, Danqing Mao, Yuanhong Liu, Zijun Xiong, Dongke Fu, Bo Li, Shuguang Wei, Xun Xu, Shengbin Li, Hui Yuan
Whole-genome shotgun (WGS) sequencing has become a routine method in genome research over the past decade. However, the assembly of highly polymorphic regions in WGS projects remains a challenge, especially for large genomes. Employing BAC library constructing, PCR screening and Sanger sequencing, traditional strategy is laborious and expensive, which hampers research on polymorphic genomic regions. As one of the most highly polymorphic regions, the major histocompatibility complex (MHC) plays a central role in the adaptive immunity of all jawed vertebrates...
2016: PloS One
https://www.readbyqxmd.com/read/27991587/a-bromodomain-dna-interaction-facilitates-acetylation-dependent-bivalent-nucleosome-recognition-by-the-bet-protein-brdt
#5
Thomas C R Miller, Bernd Simon, Vladimir Rybin, Helga Grötsch, Sandrine Curtet, Saadi Khochbin, Teresa Carlomagno, Christoph W Müller
Bromodomains are critical components of many chromatin modifying/remodelling proteins and are emerging therapeutic targets, yet how they interact with nucleosomes, rather than acetylated peptides, remains unclear. Using BRDT as a model, we characterized how the BET family of bromodomains interacts with site-specifically acetylated nucleosomes. Here we report that BRDT interacts with nucleosomes through its first (BD1), but not second (BD2) bromodomain, and that acetylated histone recognition by BD1 is complemented by a bromodomain-DNA interaction...
December 19, 2016: Nature Communications
https://www.readbyqxmd.com/read/27903752/hexim1-as-a-robust-pharmacodynamic-marker-for-monitoring-target-engagement-of-bet-family-bromodomain-inhibitors-in-tumors-and-surrogate-tissues
#6
Xiaoyu Lin, Xiaoli Huang, Tamar Uziel, Paul Hessler, Daniel H Albert, Lisa A Roberts-Rapp, Keith F McDaniel, Warren M Kati, Yu Shen
An increasing number of BET family protein inhibitors have recently entered clinical trials. It has been reported that attempts of monitoring target engagement of the BET bromodomain inhibitor OTX015 using literature-described putative pharmacodynamic (PD) markers such as c-Myc, BRD2, etc. failed to detect PD marker responses in AML patients treated at active dose and those with clinical responses. Here we report the identification and characterization of HEXIM1 and other genes as robust PD markers for BET inhibitors...
November 30, 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/27898717/gene-based-genome-wide-association-analysis-in-european-and-asian-populations-identified-novel-genes-for-rheumatoid-arthritis
#7
Hong Zhu, Wei Xia, Xing-Bo Mo, Xiang Lin, Ying-Hua Qiu, Neng-Jun Yi, Yong-Hong Zhang, Fei-Yan Deng, Shu-Feng Lei
OBJECTIVE: Rheumatoid arthritis (RA) is a complex autoimmune disease. Using a gene-based association research strategy, the present study aims to detect unknown susceptibility to RA and to address the ethnic differences in genetic susceptibility to RA between European and Asian populations. METHODS: Gene-based association analyses were performed with KGG 2.5 by using publicly available large RA datasets (14,361 RA cases and 43,923 controls of European subjects, 4,873 RA cases and 17,642 controls of Asian Subjects)...
2016: PloS One
https://www.readbyqxmd.com/read/27865874/bromodomain-containing-protein-2-induces-insulin-resistance-via-the-mtor-akt-signaling-pathway-and-an-inflammatory-response-in-adipose-tissue
#8
Ruixin Sun, Yi Wu, Weihua Hou, Zujun Sun, Yuxiong Wang, Huanhuan Wei, Wei Mo, Min Yu
Insulin resistance is a major metabolic abnormality in a large majority of patients with type II diabetes. Bromodomain-containing protein 2 (Brd2), a transcriptional co-activator/co-repressor with switch mating type/sucrose non-fermenting (SWI/SNF)-like functions that regulates chromatin, suppresses adipocyte differentiation and regulates pancreatic β-cell biology. However, the effects of Brd2 on insulin resistance remain unknown. Here, overexpression of Brd2 in white adipose tissue of wild-type (WT) mice led to insulin resistance...
January 2017: Cellular Signalling
https://www.readbyqxmd.com/read/27835869/otx015-mk-8628-a-novel-bet-inhibitor-exhibits-antitumor-activity-in-non-small-cell-and-small-cell-lung-cancer-models-harboring-different-oncogenic-mutations
#9
Maria E Riveiro, Lucile Astorgues-Xerri, Ramiro Vazquez, Roberta Frapolli, Ivo Kwee, Andrea Rinaldi, Elodie Odore, Keyvan Rezai, Mohamed Bekradda, Giorgio Inghirami, Maurizio D'Incalci, Kay Noel, Esteban Cvitkovic, Eric Raymond, Francesco Bertoni
Inhibitors targeting epigenetic control points of oncogenes offer a potential mean of blocking tumor progression in small cell and non-small cell lung carcinomas (SCLC, NSCLC). OTX015 (MK-8628) is a BET inhibitor selectively blocking BRD2/3/4. OTX015 was evaluated in a panel of NSCLC or SCLC models harboring different oncogenic mutations. Cell proliferation inhibition and cell cycle arrest were seen in sensitive NSCLC cells. MYC and MYCN were downregulated at both the mRNA and protein levels. In addition, OTX015-treatment significantly downregulated various stemness cell markers, including NANOG, Musashi-1, CD113 and EpCAM in H3122-tumors in vivo...
November 7, 2016: Oncotarget
https://www.readbyqxmd.com/read/27827996/the-bromodomain-and-extra-terminal-domain-bet-family-functional-anatomy-of-bet-paralogous-proteins
#10
REVIEW
Yasushi Taniguchi
The Bromodomain and Extra-Terminal Domain (BET) family of proteins is characterized by the presence of two tandem bromodomains and an extra-terminal domain. The mammalian BET family of proteins comprises BRD2, BRD3, BRD4, and BRDT, which are encoded by paralogous genes that may have been generated by repeated duplication of an ancestral gene during evolution. Bromodomains that can specifically bind acetylated lysine residues in histones serve as chromatin-targeting modules that decipher the histone acetylation code...
November 7, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27783056/metabolic-response-to-xd14-treatment-in-human-breast-cancer-cell-line-mcf-7
#11
Daqiang Pan, Michel Kather, Lucas Willmann, Manuel Schlimpert, Christoph Bauer, Simon Lagies, Karin Schmidtkunz, Steffen U Eisenhardt, Manfred Jung, Stefan Günther, Bernd Kammerer
XD14 is a 4-acyl pyrrole derivative, which was discovered by a high-throughput virtual screening experiment. XD14 inhibits bromodomain and extra-terminal domain (BET) proteins (BRD2, BRD3, BRD4 and BRDT) and consequently suppresses cell proliferation. In this study, metabolic profiling reveals the molecular effects in the human breast cancer cell line MCF-7 (Michigan Cancer Foundation-7) treated by XD14. A three-day time series experiment with two concentrations of XD14 was performed. Gas chromatography-mass spectrometry (GC-MS) was applied for untargeted profiling of treated and non-treated MCF-7 cells...
October 24, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27769357/clinical-trials-for-bet-inhibitors-run-ahead-of-the-science
#12
REVIEW
Guillaume Andrieu, Anna C Belkina, Gerald V Denis
Several cancer clinical trials for small molecule inhibitors of BET bromodomain proteins have been initiated. There is enthusiasm for the anti-proliferative effect of inhibiting BRD4, one of the targets of these inhibitors, which is thought to cooperate with MYC, a long-desired target for cancer therapeutics. However, no current inhibitor is selective for BRD4 among the three somatic BET proteins, which include BRD2 and BRD3; their respective functions are partially overlapping and none are functionally redundant with BRD4...
March 2016: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/27769353/erythropoiesis-provides-a-brd-s-eye-view-of-bet-protein-function
#13
REVIEW
Aaron J Stonestrom, Sarah C Hsu, Michael T Werner, Gerd A Blobel
Pharmacologic inhibitors of the bromodomain and extra-terminal motif (BET) protein family are in clinical trials for the treatment of hematologic malignancies, yet the functions of individual BET proteins remain largely uncharacterized. We review the molecular roles of BETs in the context of erythropoiesis. Studies in this lineage have provided valuable insights into their mechanisms of action, and helped define the individual and overlapping functions of BET protein family members BRD2, BRD3, and BRD4. These studies have important ramifications for our understanding of the molecular and physiologic roles of BET proteins, and provide a framework for elucidating some of the beneficial and adverse effects of pharmacologic inhibitors...
March 2016: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/27769352/phospho-brd4-transcription-plasticity-and-drug-targeting
#14
REVIEW
Cheng-Ming Chiang
BRD4 is an epigenetic regulator and transcription cofactor whose phosphorylation by CK2 and dephosphorylation by PP2A modulates its function in chromatin targeting, factor recruitment, and cancer progression. While the bromodomains of BET family proteins, including BRD4, BRD2, BRD3 and BRDT, have been the primary targets of small compounds such as JQ1, I-BET and MS417 that show promising anticancer effects against some hematopoietic cancer and solid tumors, drug resistance upon prolonged treatment necessitates a better understanding of alternative pathways underlying not only the resistance but also persistent BET protein dependence for identifying new targets and effective combination therapy strategies...
March 2016: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/27651315/brd4-regulates-breast-cancer-dissemination-through-jagged1-notch1-signaling
#15
Guillaume Andrieu, Anna H Tran, Katherine J Strissel, Gerald V Denis
The bromodomain and extraterminal (BET) proteins are epigenetic "readers" of acetylated histones in chromatin and have been identified as promising therapeutic targets in diverse cancers. However, it remains unclear how individual family members participate in cancer progression and small molecule inhibitors such as JQ1 can target functionally independent BET proteins. Here, we report a signaling pathway involving BRD4 and the ligand/receptor pair Jagged1/Notch1 that sustains triple-negative breast cancer migration and invasion...
September 20, 2016: Cancer Research
https://www.readbyqxmd.com/read/27591477/bet-bromodomain-inhibition-promotes-neurogenesis-while-inhibiting-gliogenesis-in-neural-progenitor-cells
#16
Jingjun Li, Jing Ma, Guofeng Meng, Hong Lin, Sharon Wu, Jamie Wang, Jie Luo, Xiaohong Xu, David Tough, Matthew Lindon, Inmaculada Rioja, Jing Zhao, Hongkang Mei, Rab Prinjha, Zhong Zhong
Neural stem cells and progenitor cells (NPCs) are increasingly appreciated to hold great promise for regenerative medicine to treat CNS injuries and neurodegenerative diseases. However, evidence for effective stimulation of neuronal production from endogenous or transplanted NPCs for neuron replacement with small molecules remains limited. To identify novel chemical entities/targets for neurogenesis, we had established a NPC phenotypic screen assay and validated it using known small-molecule neurogenesis inducers...
September 2016: Stem Cell Research
https://www.readbyqxmd.com/read/27451123/small-molecule-targeting-of-bet-proteins-in-cancer
#17
C A French
BET proteins have recently become recognized for their role in a broad range of cancers and are defined by the presence of two acetyl-histone reading bromodomains and an ET domain. This family of proteins includes BRD2, BRD3, BRD4, and BRDT. BRD4 is the most-studied BET protein in cancer, and normally serves as an epigenetic reader that links active chromatin marks to transcriptional elongation through activation of RNA polymerase II. The role of BRD3 and BRD4 first became known in cancer as mutant oncoproteins fused to the p300-recruiting NUT protein in a rare aggressive subtype of squamous cell cancer known as NUT midline carcinoma (NMC)...
2016: Advances in Cancer Research
https://www.readbyqxmd.com/read/27388964/otx015-mk-8628-a-novel-bet-inhibitor-displays-in-vitro-and-in-vivo-antitumor-effects-alone-and-in-combination-with-conventional-therapies-in-glioblastoma-models
#18
Caroline Berenguer-Daizé, Lucile Astorgues-Xerri, Elodie Odore, Mylène Cayol, Esteban Cvitkovic, Kay Noel, Mohamed Bekradda, Sarah MacKenzie, Keyvan Rezai, François Lokiec, Maria E Riveiro, L'Houcine Ouafik
Bromodomain and extraterminal (BET) bromodomain (BRD) proteins are epigenetic readers that bind to acetylated lysine residues on chromatin, acting as co-activators or co-repressors of gene expression. BRD2 and BRD4, members of the BET family, are significantly increased in glioblastoma multiforme (GBM), the most common primary adult brain cancer. OTX015 (MK-8628), a novel BRD2/3/4 inhibitor, is under evaluation in dose-finding studies in solid tumors, including GBM. We investigated the pharmacologic characteristics of OTX015 as a single agent and combined with targeted therapy or conventional chemotherapies in glioblastoma cell lines...
November 1, 2016: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/27308593/histone-variant-h2a-z-2-a-novel-driver-of-melanoma-progression
#19
Chiara Vardabasso, Sandra B Hake, Emily Bernstein
Histone variants are attracting attention in the field of cancer epigenetics. Our study has established a novel role for the uncharacterized histone variant H2A.Z.2 as a driver of malignant melanoma. H2A.Z.2 promotes cellular proliferation by recruiting BRD2 and E2F1 to E2F target genes and facilitating their transcription. High H2A.Z.2 expression correlates with poor survival in patients, and its depletion sensitizes cells to chemotherapy and targeted therapies.
March 2016: Molecular & Cellular Oncology
https://www.readbyqxmd.com/read/27282480/rvx-297-a-novel-bd2-selective-inhibitor-of-bet-bromodomains
#20
Olesya A Kharenko, Emily M Gesner, Reena G Patel, Karen Norek, Andre White, Eric Fontano, Robert K Suto, Peter R Young, Kevin G McLure, Henrik C Hansen
Bromodomains are epigenetic readers that specifically bind to the acetyl lysine residues of histones and transcription factors. Small molecule BET bromodomain inhibitors can disrupt this interaction which leads to potential modulation of several disease states. Here we describe the binding properties of a novel BET inhibitor RVX-297 that is structurally related to the clinical compound RVX-208, currently undergoing phase III clinical trials for the treatment of cardiovascular diseases, but is distinctly different in its biological and pharmacokinetic profiles...
August 12, 2016: Biochemical and Biophysical Research Communications
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