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BRD2 OR BRD3 OR BRD4 OR JQ1

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https://www.readbyqxmd.com/read/29333921/targeting-brd4-proteins-suppresses-the-growth-of-nsclc-through-downregulation-of-eif4e-expression
#1
Zhongyuan Gao, Ting Yuan, Xiao Zhou, Ping Ni, Geng Sun, Ping Li, Zhixiang Cheng, Xuerong Wang
Lung cancer is the leading cause of cancer-related death worldwide. Bromodomain and extraterminal domain (BET) proteins act as epigenome readers for gene transcriptional regulation. Among BET family members, BRD4 was well studied, but for its mechanism in non-small cell lung carcinoma has not been elucidated. eIF4E regulates gene translation and has been proved to play an important role in the progression of lung cancer. In this study, we first confirmed that BET inhibitors JQ1 and I-BET151 suppressed the growth of NSCLCs, in parallel with downregulated eIF4E expression...
January 15, 2018: Cancer Biology & Therapy
https://www.readbyqxmd.com/read/29321313/tip60-complex-inhibits-hbv-transcription
#2
Hironori Nishitsuji, Saneyuki Ujino, Keisuke Harada, Kunitada Shimotohno
Hepatitis B virus (HBV) is a global major health problem with over one million deaths annually caused by chronic liver damage. Understanding host factors that modulate HBV replication may aid the development of anti-HBV therapies. Our recent genome-wide small interfering RNA screen using recombinant HBV demonstrated that TIP60 inhibited HBV infection. Here, we show that TIP60 complex contributes to anti-HBV defense. The TIP60 complex bound to the HBV promoter and suppressed HBV transcription driven by the precore/core promoter...
January 10, 2018: Journal of Virology
https://www.readbyqxmd.com/read/29312470/combined-inhibition-of-bet-proteins-and-class-i-hdacs-synergistically-induces-apoptosis-in-urothelial-carcinoma-cell-lines
#3
Alexander S Hölscher, Wolfgang A Schulz, Maria Pinkerneil, Günter Niegisch, Michèle J Hoffmann
Background: New efficient therapies for urothelial carcinoma (UC) are urgently required. Small-molecule drugs targeting chromatin regulators are reasonable candidates because these regulators are frequently mutated or deregulated in UC. Indeed, in previous work, Romidepsin, which targets class I histone deacetylases (HDAC), efficiently killed UC cells, but did not elicit canonical apoptosis and affected benign urothelial cells indiscriminately. Combinations of HDAC inhibitors with JQ1, an inhibitor of bromodomain-containing acetylation reader proteins like BRD4, which promote especially the transcription of pro-tumorigenic genes, have shown efficacy in several tumor types...
2018: Clinical Epigenetics
https://www.readbyqxmd.com/read/29303513/in-vitro-modeling-of-hepatocellular-carcinoma-molecular-subtypes-for-anti-cancer-drug-assessment
#4
Hadassa Hirschfield, C Billie Bian, Takaaki Higashi, Shigeki Nakagawa, Tizita Z Zeleke, Venugopalan D Nair, Bryan C Fuchs, Yujin Hoshida
Tractable experimental model that accounts for inter-tumor molecular heterogeneity is a key element of anti-cancer drug development. Hepatocellular carcinoma is known to exhibit highly heterogeneous molecular aberrations across the tumors, including somatic genetic and epigenetic alterations. Previous studies showed that molecular tumor subtypes determined by transcriptome, as a comprehensive functional readout, are reproducibly observed across global patient populations irrespective of geographic and etiological variations...
January 5, 2018: Experimental & Molecular Medicine
https://www.readbyqxmd.com/read/29298799/targeting-her2-aberrations-in-non-small-cell-lung-cancer-with-osimertinib
#5
Shengwu Liu, Shuai Li, Josephine Hai, Xiaoen Wang, Ting Chen, Max M Quinn, Peng Gao, Yanxi Zhang, Hongbin Ji, Darren Cross, Kwok-Kin Wong
PURPOSE: HER2 (or ERBB2) aberrations, including both amplification and mutations, have been classified as oncogenic drivers that contribute to 2-6 percent of lung adenocarcinomas. HER2 amplification is also an important mechanism for acquired resistance to EGFR tyrosine kinase inhibitors (TKIs). However, due to limited preclinical studies and clinical trials, currently there is still no available standard of care for lung cancer patients with HER2 aberrations. To fulfill the clinical need for targeting HER2 in non-small cell lung cancer (NSCLC) patients, we performed a comprehensive pre-clinical study to evaluate the efficacy of a third-generation TKI, osimertinib (AZD9291)...
January 3, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29298347/predicting-effective-pro-apoptotic-anti-leukaemic-drug-combinations-using-co-operative-dynamic-bh3-profiling
#6
Martin Grundy, Claire Seedhouse, Thomas Jones, Liban Elmi, Michael Hall, Adam Graham, Nigel Russell, Monica Pallis
The BH3-only apoptosis agonists BAD and NOXA target BCL-2 and MCL-1 respectively and co-operate to induce apoptosis. On this basis, therapeutic drugs targeting BCL-2 and MCL-1 might have enhanced activity if used in combination. We identified anti-leukaemic drugs sensitising to BCL-2 antagonism and drugs sensitising to MCL-1 antagonism using the technique of dynamic BH3 profiling, whereby cells were primed with drugs to discover whether this would elicit mitochondrial outer membrane permeabilisation in response to BCL-2-targeting BAD-BH3 peptide or MCL-1-targeting MS1-BH3 peptide...
2018: PloS One
https://www.readbyqxmd.com/read/29296220/sequencing-of-lynch-syndrome-tumors-reveals-the-importance-of-epigenetic-alterations
#7
Noora Porkka, Satu Valo, Taina T Nieminen, Alisa Olkinuora, Satu Mäki-Nevala, Samuli Eldfors, Päivi Peltomäki
Genomic instability and epigenetic aberrations are important classifiers of human tumors, yet, their interrelations are poorly understood. We used Lynch syndrome (LS) to address such relationships. Forty-five tumors (11 colorectal adenomas, 18 colorectal carcinomas, and 16 ovarian carcinomas) were profiled for CpG Island Methylator Phenotype (CIMP) and somatic mutations. All tumors showed high-degree microsatellite instability. Panel sequencing of 578 cancer-relevant genes revealed the average number of 1433, 1124, and 657 non-synonymous somatic mutations per colorectal adenoma, colorectal carcinoma, and ovarian carcinoma, respectively...
December 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/29296201/autophagy-flux-inhibition-g2-m-cell-cycle-arrest-and-apoptosis-induction-by-ubenimex-in-glioma-cell-lines
#8
Liping Han, Yongfei Zhang, Shuai Liu, Qingwei Zhao, Xianhong Liang, Zhiguo Ma, Prakash K Gupta, Miaoqing Zhao, Aihua Wang
This study aimed to investigate whether ubenimex could work as an anti-tumor drug alone in glioma cells and figure out the underlying potential mechanisms. Ubenimex is widely used as an adjunct therapy in multiple solid cancers. However, it is rarely used to treat glioblastoma. The function of ubenimex in enhancing JQ1 treatment sensitivity of glioma cells by blocking autophagic degradation of HEXIM1 was previously studied. However, the detailed mechanism of autophagy regulation by ubenimex remains unclear...
December 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/29290992/oridonin-synergistically-enhances-jq1-triggered-apoptosis-in-hepatocellular-cancer-cells-through-mitochondrial-pathway
#9
Hua-Peng Zhang, Gong-Quan Li, Wen-Zhi Guo, Guang-Hui Chen, Hong-Wei Tang, Bing Yan, Jie Li, Jia-Kai Zhang, Pei-Hao Wen, Zhi-Hui Wang, Jian-Feng Lv, Shui-Jun Zhang
Bromodomain and Extra-Terminal Domain (BET) inhibitors, such as JQ1 have emerged as novel drug candidates and are being enthusiastically pursued in clinical trials for the treatment of cancer. However, many solid cancers are resistance to BET inhibitors. To explore methods for improving the therapeutic potential of BET inhibitors, we investigated the combinational activity of JQ1 with Oridonin, a bioactive molecules derived from Traditional Chinese Medicine in hepatocellular carcinoma (HCC) cells. Our results showed that Oridonin synergistically enhanced the abilities of JQ1 to inhibit cell viability in HCC cells and, significantly augmented JQ1-triggered apoptosis in HCC cells and in HCC cancer stem-like cells...
December 5, 2017: Oncotarget
https://www.readbyqxmd.com/read/29287727/upregulation-of-mcl-1-inhibits-jq1-triggered-anticancer-activity-in-hepatocellular-carcinoma-cells
#10
Hua-Peng Zhang, Gong-Quan Li, Yi Zhang, Wen-Zhi Guo, Jia-Kai Zhang, Jie Li, Jian-Feng Lv, Shui-Jun Zhang
Bromodomains and extra-terminal (BET) proteins inhibitors are promising cancer therapeutic agents. However, tumor cells often develop resistance to BET inhibitors, greatly limiting their therapeutic potential. To study the mechanism underlying the resistance of BET inhibitors in hepatocellular carcinoma (HCC) cells, we herein investigated the impact of BET inhibitor JQ1 on the gene expression of Bcl-2 family members by RNA sequencing analysis, and found that acute treatment with JQ1 triggered upregulation of Mcl-1 in HCCLM3 and BEL7402 cell lines...
December 26, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29262321/bet-bromodomain-inhibition-synergizes-with-parp-inhibitor-in-epithelial-ovarian-cancer
#11
Sergey Karakashev, Hengrui Zhu, Yuhki Yokoyama, Bo Zhao, Nail Fatkhutdinov, Andrew V Kossenkov, Andrew J Wilson, Fiona Simpkins, David Speicher, Dineo Khabele, Benjamin G Bitler, Rugang Zhang
PARP inhibition is known to be an effective clinical strategy in BRCA mutant cancers, but PARP inhibition has not been applied to BRCA-proficient tumors. Here, we show the synergy of BET bromodomain inhibition with PARP inhibition in BRCA-proficient ovarian cancers due to mitotic catastrophe. Treatment of BRCA-proficient ovarian cancer cells with the BET inhibitor JQ1 downregulated the G2-M cell-cycle checkpoint regulator WEE1 and the DNA-damage response factor TOPBP1. Combining PARP inhibitor Olaparib with the BET inhibitor, we observed a synergistic increase in DNA damage and checkpoint defects, which allowed cells to enter mitosis despite the accumulation of DNA damage, ultimately causing mitotic catastrophe...
December 19, 2017: Cell Reports
https://www.readbyqxmd.com/read/29251329/bet-bromodomain-inhibitor-jq1-modulates-microrna-expression-in-thyroid-cancer-cells
#12
Catia Mio, Ketty Conzatti, Federica Baldan, Lorenzo Allegri, Marialuisa Sponziello, Francesca Rosignolo, Diego Russo, Sebastiano Filetti, Giuseppe Damante
Anaplastic thyroid carcinoma (ATC) represents the most lethal thyroid cancer sub-type, currently unresponsive to standard treatments. Recently, bromodomain and extra-terminal (BET) proteins have emerged as attractive therapeutic targets in several diseases, including cancer. In different cancer models, the anti-neoplastic activity of BET inhibitors such as JQ1, I-BET762 and I-BET151 have already been established, due to both direct and indirect effects. miRNAs are 20-22 nucleotide transcriptional regulators which play important roles in proliferation, differentiation and apoptosis...
February 2018: Oncology Reports
https://www.readbyqxmd.com/read/29240787/brd3-4-inhibition-and-flt3-ligand-deprivation-target-pathways-that-are-essential-for-the-survival-of-human-mll-af9-leukemic-cells
#13
Marco Carretta, Annet Z Brouwers-Vos, Matthieu Bosman, Sarah J Horton, Joost H A Martens, Edo Vellenga, Jan Jacob Schuringa
In the present work we aimed to identify targetable signaling networks in human MLL-AF9 leukemias. We show that MLL-AF9 cells critically depend on FLT3-ligand induced pathways as well as on BRD3/4 for their survival. We evaluated the in vitro and in vivo efficacy of the BRD3/4 inhibitor I-BET151 in various human MLL-AF9 (primary) models and patient samples and analyzed the transcriptome changes following treatment. To further understand the mode of action of BRD3/4 inhibition, we performed ChIP-seq experiments on the MLL-AF9 complex in THP1 cells and compared it to RNA-seq data of I-BET151 treated cells...
2017: PloS One
https://www.readbyqxmd.com/read/29239081/development-and-validation-of-2d-difference-intensity-analysis-for-chemical-library-screening-by-protein-detected-nmr
#14
John M Egner, Davin R Jensen, Mike D Olp, Nolan W Kennedy, Brian F Volkman, Francis C Peterson, Brian C Smith, R Blake Hill
An academic chemical screening approach was developed and a 352-chemical fragment library screened against 3 different protein targets using 2D protein-detected NMR. The approach was optimized against 2 protein targets with known ligands, CXCL12 and BRD4. Principal component analysis reliably identified compounds that induced NMR crosspeak broadening, but did not unambiguously identify ligands with specific affinity (hits). For improved hit detection, a novel scoring metric - difference intensity analysis (DIA) - was devised that sums all positive and negative intensities from 2D difference spectra...
December 13, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/29237530/-mechanism-of-action-of-bet-bromodomain-inhibitor-jq1-in-treating-airway-remodeling-in-asthmatic-mice
#15
Xiao-Hua Zhu, Qiu-Gen Li, Jun Wang, Guo-Zhu Hu, Zhi-Qiang Liu, Qing-Hua Hu, Gang Wu
OBJECTIVE: To investigate the molecular mechanism of action of BET bromodomain inhibitor JQ1 in treating airway remodeling in asthmatic mice. METHODS: A total of 24 mice were randomly divided into control group, ovalbumin (OVA)-induced asthma group (OVA group), and JQ1 intervention group (JQ1+OVA group), with 8 mice in each group. OVA sensitization/challenge was performed to establish a mouse model of asthma. At 1 hour before challenge, the mice in the JQ1+OVA group were given intraperitoneal injection of JQ1 solution (50 μg/g)...
December 2017: Zhongguo Dang Dai Er Ke za Zhi, Chinese Journal of Contemporary Pediatrics
https://www.readbyqxmd.com/read/29233295/novel-approaches-to-targeting-brd4
#16
REVIEW
Olesya A Kharenko, Henrik C Hansen
Inhibition of bromo and extra-terminal (BET) bromodomains, including BRD4, has emerged as a new exciting epigenetic target for oncology, in particular. Recently, novel alternatives to the traditional use of reversible small molecules have emerged, including proteolytic targeting BET agents and irreversible binding inhibitors. These alternatives to reversible inhibitors may offer some advantage and can be used as tools to further decipher the underlying biology. Supportive pre-clinical data have these novel approaches bound for clinical development in the near future...
June 2017: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/29228979/contrasting-effect-of-the-latency-reversing-agents-bryostatin-1-and-jq1-on-astrocyte-mediated-neuroinflammation-and-brain-neutrophil-invasion
#17
Alizé Proust, Corinne Barat, Mathieu Leboeuf, Jean Drouin, Michel J Tremblay
BACKGROUND: Despite effectiveness of the combined antiretroviral therapy, HIV-1 persists in long-lived latently infected cells. Consequently, new therapeutic approaches aimed at eliminating this latent reservoir are currently being developed. A "shock and kill" strategy using latency-reversing agents (LRA) to reactivate HIV-1 has been proposed. However, the impact of LRA on the central nervous system (CNS) remains elusive. METHODS: We used human fetal astrocytes and investigated the effects of several LRA on their functional and secretory activities...
December 11, 2017: Journal of Neuroinflammation
https://www.readbyqxmd.com/read/29228703/dual-inhibition-of-brd4-and-pi3k-akt-by-sf2523-suppresses-human-renal-cell-carcinoma-cell-growth
#18
Hua Zhu, Jia-Hui Mao, Yin Wang, Dong-Hua Gu, Xiao-Dong Pan, Yuxi Shan, Bing Zheng
Bromodomain-containing protein 4 (BRD4) and PI3K-AKT are both important for renal cell carcinoma (RCC) development and progression. SF2523 is a BRD4 and PI3K-AKT dual inhibitor. The present study demonstrated that SF2523 was cytotoxic and anti-proliferative to established RCC cell lines (786-O and A498) and primary human RCC cells. SF2523 induced activation of caspase and apoptosis in RCC cells. Further, SF2523 disrupted RCC cell cycle progression and inhibited cell migration in vitro. At the signaling level, SF2523 in-activated PI3K-AKT-mTOR, and downregulated BRD4-dependent proteins, Bcl-2 and Myc, in RCC cells...
November 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29208683/il-33-and-st2-mediate-fak-dependent-antitumor-immune-evasion-through-transcriptional-networks
#19
Bryan Serrels, Niamh McGivern, Marta Canel, Adam Byron, Sarah C Johnson, Henry J McSorley, Niall Quinn, David Taggart, Alex Von Kreigsheim, Stephen M Anderton, Alan Serrels, Margaret C Frame
Focal adhesion kinase (FAK) mediates tumor cell-intrinsic behaviors that promote tumor growth and metastasis. We previously showed that FAK also induces the expression of inflammatory genes that inhibit antitumor immunity in the microenvironment. We identified a crucial, previously unknown role for the dual-function cytokine interleukin-33 (IL-33) in FAK-dependent immune evasion. In murine squamous cell carcinoma (SCC) cells, specifically nuclear FAK enhanced the expression of the genes encoding IL-33, the chemokine CCL5, and the soluble, secreted form of the IL-33 receptor, called soluble ST2 (sST2)...
December 5, 2017: Science Signaling
https://www.readbyqxmd.com/read/29196562/the-role-of-bromodomain-and-extraterminal-motif-bet-proteins-in-chromatin-structure
#20
Sarah C Hsu, Gerd A Blobel
Bromodomain and extraterminal motif (BET) proteins have been widely investigated for their roles in gene regulation and their potential as therapeutic targets in cancer. Pharmacologic BET inhibitors target the conserved bromodomain-acetyllysine interaction and do not distinguish between BRD2, BRD3, and BRD4. Thus, comparatively little is known regarding the distinct roles played by individual family members, as well as the underlying mechanisms that drive the transcriptional effects of BET inhibitors. Here we review studies regarding the contributions of BET proteins to genome structure and function, including recent work identifying a role for BRD2 as a component of functional and physical chromatin domain boundaries...
December 1, 2017: Cold Spring Harbor Symposia on Quantitative Biology
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