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Hiroyuki Yamauchi, Kazue Honma, Kazuki Mochizuki, Toshinao Goda
Jejunal sodium/glucose co-transporter (Sglt1) displays circadian expression. The jejunum was collected every 4 h from mice, and we examined histone acetylation and binding of bromodomain-containing protein-4 (BRD4) around of the gene. Histone acetylation increased in the transcribed region of Sglt1 prior to induction of the gene. Furthermore, the binding of mRNA elongation factor around the gene showed circadian rhythm.
March 20, 2018: Bioscience, Biotechnology, and Biochemistry
Jonathan Welti, Adam Sharp, Wei Yuan, David I Dolling, Daniel Nava Rodrigues, Ines Figueiredo, Veronica Gil, Antje Neeb, Matthew Clarke, George Seed, Mateus Crespo, Semini Sumanasuriya, Jian Ning, Eleanor Knight, Jeffrey C Francis, Ashley Hughes, Wendy S Halsey, Alec Paschalis, Ram S Mani, Ganesh V Raj, Steve Plymate, Suzanne Carreira, Gunther Boysen, Arul M Chinnaiyan, Amanda Swain, Johann S de Bono
PURPOSE:  Persistent androgen receptor (AR) signaling drives castration resistant prostate cancer (CRPC) and confers resistance to AR targeting therapies. Novel therapeutic strategies to overcome this are urgently required. We evaluated how bromodomain and extra-terminal (BET) protein inhibitors (BETi) abrogate aberrant AR signaling in CRPC. EXPERIMENTAL DESIGN:  We determined associations between BET expression, AR driven transcription and patient outcome; and the effect and mechanism by which chemical BETi (JQ1 and GSK1210151A; I-BET151) and BET family protein knockdown regulates AR-V7 expression and AR signaling in prostate cancer (PC) models...
March 19, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Min Huang, Li Zhu, Jacqueline S Garcia, Michael X Li, Andrew J Gentles, Beverly S Mitchell
We have recently reported that activation of Brd4 is associated with the presence of autophagy in NPMc+ and MLL AML cells. In order to determine the mechanisms underlying this relationship, we have examined the role of Brd4 in regulating the expression of several genes that are central to the process of autophagy. We found that Brd4 binds to the promoters of ATG 3, 7 and CEBPβ, and expression of these genes is markedly reduced by inhibitors of Brd4, as well as by Brd4-shRNA and depletion of CEBPβ. Inhibitors of Brd4 also dramatically suppress the transcription of Keap1, thereby increasing the expression of anti-oxidant genes through the Nrf2 pathway and reducing the cytotoxicity induced by Brd4 inhibitors...
February 20, 2018: Oncotarget
Qiuping Xiang, Yan Zhang, Jiaguo Li, Xiaoqian Xue, Chao Wang, Ming Song, Cheng Zhang, Rui Wang, Chenchang Li, Chun Wu, Yulai Zhou, Xiaohong Yang, Guohui Li, Ke Ding, Yong Xu
Prostate cancer is a commonly diagnosed cancer and a leading cause of cancer-related deaths. The bromodomain and extra terminal domain (BET) family proteins have emerged as potential therapeutic targets for the treatment of castration-resistant prostate cancer. A series of 2,2-dimethyl-2 H -benzo[ b ][1,4]oxazin-3(4 H )-one derivatives were designed and synthesized as selective bromodomain containing protein 4 (BRD4) inhibitors. The compounds potently inhibit BRD4(1) with nanomolar IC50 values and exhibit high selectivity over most non-BET subfamily members...
March 8, 2018: ACS Medicinal Chemistry Letters
Erina Tonouchi, Yasuyuki Gen, Tomoki Muramatsu, Hidekazu Hiramoto, Kousuke Tanimoto, Jun Inoue, Johji Inazawa
Bromodomain Containing 4 (BRD4) mediates transcriptional elongation of the oncogene MYC by binding to acetylated histones. BRD4 has been shown to play a critical role in tumorigenesis in several cancers, and the BRD4-NUT fusion gene is a driver of NUT midline carcinoma (NMC), a rare but highly lethal cancer. microRNAs (miRNAs) are endogenous small non-coding RNAs that suppress target gene expression by binding to complementary mRNA sequences. Here, we show that miR-3140, which was identified as a novel tumor suppressive miRNA by function-based screening of a library containing 1090 miRNA mimics, directly suppressed BRD4 by binding to its coding sequence (CDS)...
March 14, 2018: Scientific Reports
Chaoyang Sun, Jun Yin, Yong Fang, Jian Chen, Kang Jin Jeong, Xiaohua Chen, Christopher P Vellano, Zhenlin Ju, Wei Zhao, Dong Zhang, Yiling Lu, Funda Meric-Bernstam, Timothy A Yap, Maureen Hattersley, Mark J O'Connor, Huawei Chen, Stephen Fawell, Shiaw-Yih Lin, Guang Peng, Gordon B Mills
Poly(ADP-ribose) polymerase inhibitors (PARPi) are selectively active in cells with homologous recombination (HR) deficiency (HRD) caused by mutations in BRCA1, BRCA2, and other pathway members. We sought small molecules that induce HRD in HR-competent cells to induce synthetic lethality with PARPi and extend the utility of PARPi. We demonstrated that inhibition of bromodomain containing 4 (BRD4) induced HRD and sensitized cells across multiple tumor lineages to PARPi regardless of BRCA1/2, TP53, RAS, or BRAF mutation status through depletion of the DNA double-stand break resection protein CtIP (C-terminal binding protein interacting protein)...
March 12, 2018: Cancer Cell
Laurent Batiste, Andrea Unzue, Aymeric Dolbois, Fabrice Hassler, Xuan Wang, Nicholas Deerain, Jian Zhu, Dimitrios Spiliotopoulos, Cristina Nevado, Amedeo Caflisch
Expanding the chemical space and simultaneously ensuring synthetic accessibility is of upmost importance, not only for the discovery of effective binders for novel protein classes but, more importantly, for the development of compounds against hard-to-drug proteins. Here, we present AutoCouple, a de novo approach to computational ligand design focused on the diversity-oriented generation of chemical entities via virtual couplings. In a benchmark application, chemically diverse compounds with low-nanomolar potency for the CBP bromodomain and high selectivity against the BRD4(1) bromodomain were achieved by the synthesis of about 50 derivatives of the original fragment...
February 28, 2018: ACS Central Science
Jianping Hu, Yingqing Wang, Yanlian Li, Danyan Cao, Lin Xu, ShanShan Song, Mohammadali Soleimani Damaneh, Jian Li, Yuelei Chen, Xin Wang, Lin Chen, Jingkang Shen, Zehong Miao, Bing Xiong
Recently, several kinase inhibitors were found to also inhibit bromodomains, providing a new strategy for the discovery of bromodomain inhibitors. Along this line, starting from PLK1-BRD4 dual inhibitor BI-2536, we discovered a new series of dihydroquinoxalin-2(1H)-one with aniline and indoline WPF binders as selective BRD4 inhibitors. They showed better BRD4-BD1 potency and negligible PLK1 kinase activity comparing with BI-2536. Additionally, dihydroquinoxalin-2(1H)-ones containing indoline group showed profound activities in molecular and cellular based assays...
February 24, 2018: European Journal of Medicinal Chemistry
Morgan Preziosi, Minakshi Poddar, Sucha Singh, Satdarshan P Monga
Activation of the Wnt/β-catenin signaling is reported in large subsets of hepatocellular carcinoma (HCC). Upregulationof Wnt genes is one contributing mechanism. In the current study, we sought to address the role of hepatocyte-derived Wnts in a model of hepatic injury, fibrosis and carcinogenesis. We subjected hepatocyte-specific Wntless knockout mice (HP-KO), unable to secrete Wnts from hepatocytes, and littermate controls (HP-CON), to diethylnitrosamine and carbon tetrachloride (DEN/CCl4) and harvested at 3, 5, and 6 months for histological and molecular analysis...
March 8, 2018: Gene Expression
Emilia Kuuluvainen, Eva Domènech-Moreno, Elina H Niemelä, Tomi P Mäkelä
In cancer, oncogene activation is partly mediated by acquired super-enhancers therefore representing potential targets for inhibition. Super-enhancers are enriched for BRD4 and Mediator and both BRD4 and the Mediator MED12 subunit are disproportionally required for expression of super-enhancer associated genes in stem cells. Here, we find that depletion of Mediator kinase module subunits MED12, and MED13 with MED13L, can be used to reduce expression of cancer acquired super-enhancer genes such as MYC in colon cancer cells with a concomitant decrease in proliferation...
March 5, 2018: Molecular and Cellular Biology
Noelia Luna-Peláez, Mario García-Domínguez
During development, cellular differentiation programs need of tight regulation for proper display of the activity of multiple factors in time and space. Chromatin adaptors of the BET family (Brd2, Brd3, Brd4 and Brdt in vertebrates) are transcription co-regulators tightly associated with the progression of the cell cycle. A key question regarding their function is whether they work as part of the general transcription machinery or, on the contrary, they are precisely recruited to the chromatin through specific transcription factors...
March 2, 2018: Journal of Molecular Biology
Guillaume P Andrieu, Jordan S Shafran, Jude T Deeney, Kishan R Bharadwaj, Annapoorni Rangarajan, Gerald V Denis
Obesity and its associated pathology Type 2 diabetes are two chronic metabolic and inflammatory diseases that promote breast cancer progression, metastasis, and poor outcomes. Emerging critical opinion considers unresolved inflammation and abnormal metabolism separately from obesity; settings where they do not co-occur can inform disease mechanism. In breast cancer, the tumor microenvironment is often infiltrated with T effector and T regulatory cells programmed by metabolic signaling. The pathways by which tumor cells evade immune surveillance, immune therapies, and take advantage of antitumor immunity are poorly understood, but likely depend on metabolic inflammation in the microenvironment...
March 1, 2018: Journal of Leukocyte Biology
Aishwarya Pawar, Paradesi Naidu Gollavilli, Shaomeng Wang, Irfan A Asangani
BRD4 plays a major role in the transcription networks orchestrated by androgen receptor (AR) in castration-resistant prostate cancer (CRPC). Several BET inhibitors (BETi) that displace BRD4 from chromatin are being evaluated in clinical trials for CRPC. Here, we describe mechanisms of acquired resistance to BETi that are amenable to targeted therapies in CRPC. BETi-resistant CRPC cells displayed cross-resistance to a variety of BETi in the absence of gatekeeper mutations, exhibited reduced chromatin-bound BRD4, and were less sensitive to BRD4 degraders/knockdown, suggesting a BRD4-independent transcription program...
February 27, 2018: Cell Reports
Courtney G Sansam, Katarzyna Pietrzak, Blanka Majchrzycka, Maciej A Kerlin, Jingrong Chen, Susannah Rankin, Christopher L Sansam
DNA replication origins in hyperacetylated euchromatin fire preferentially during early S phase. However, how acetylation controls DNA replication timing is unknown. TICRR/TRESLIN is an essential protein required for the initiation of DNA replication. Here, we report that TICRR physically interacts with the acetyl-histone binding bromodomain (BRD) and extraterminal (BET) proteins BRD2 and BRD4. Abrogation of this interaction impairs TICRR binding to acetylated chromatin and disrupts normal S-phase progression...
February 26, 2018: Genes & Development
Grant R Campbell, Rachel S Bruckman, Shayna D Herns, Shweta Joshi, Donald Durden, Stephen A Spector
In this study, we investigated the effect of the dual phosphatidylinositol 3-kinase/mechanistic target of rapamycin (PI3K/MTOR) inhibitor dactolisib (NVP-BEZ235), the PI3K/ MTOR/bromodomain-containing protein 4 (BRD4) inhibitor SF2523 and the BET inhibitor JQ1 on the productive infection of primary macrophages with human immunodeficiency type-1 (HIV). These inhibitors did not alter the initial susceptibility of macrophages to HIV infection. However, dactolisib, JQ1 and SF2523 all decreased HIV replication in macrophages in a dose dependent manner via degradation of intracellular HIV through autophagy...
February 23, 2018: Journal of Biological Chemistry
Duncan C Miller, Mathew P Martin, Santosh Adhikari, Alfie Brennan, Jane A Endicott, Bernard T Golding, Ian R Hardcastle, Amy Heptinstall, Stephen Hobson, Claire Jennings, Lauren Molyneux, Yvonne Ng, Stephen R Wedge, Martin E M Noble, Celine Cano
ATAD2 is an ATPase that is overexpressed in a variety of cancers and associated with a poor patient prognosis. This protein has been suggested to function as a cofactor for a range of transcription factors, including the proto-oncogene MYC and the androgen receptor. ATAD2 comprises an ATPase domain, implicated in chromatin remodelling, and a bromodomain which allows it to interact with acetylated histone tails. Dissection of the functional roles of these two domains would benefit from the availability of selective, cell-permeable pharmacological probes...
February 22, 2018: Organic & Biomolecular Chemistry
Keiya Takahashi, Hyun Yi, Ching-Hang Liu, Shue Liu, Yuta Kashiwagi, Dennis J Patin, Shuanglin Hao
The symptoms of HIV-sensory neuropathy are dominated by neuropathic pain. Recent data show that repeated use of opiates enhances the chronic pain states in HIV patients. Limited attention has so far been devoted to exploring the exact pathogenesis of HIV painful disorder and opiate abuse in vivo, for which there is no effective treatment. Bromodomain-containing protein 4 (Brd4) is a member of the bromodomain and extraterminal domain protein (BET) family and functions as a chromatin 'reader' that binds acetylated lysines in histones in brain neurons to mediate the transcriptional regulation underlying learning and memory...
February 20, 2018: Neuroreport
Valérie Bernard, Chiara Villa, Aurélie Auguste, Sophie Lamothe, Anne Guillou, Agnès Martin, Sandrine Caburet, Jacques Young, Reiner A Veitia, Nadine Binart
Lactotroph adenoma, also called prolactinoma, is the most common pituitary tumor but little is known about its pathogenesis. Mouse models of prolactinoma can be useful to better understand molecular mechanisms involved in abnormal lactotroph cell proliferation and secretion. We have previously developed a prolactin receptor deficient ( Prlr -/- ) mouse, which develops prolactinoma. The present study aims to explore the natural history of prolactinoma formation in Prlr -/- mice, using hormonal, radiological, histological and molecular analyses to uncover mechanisms involved in lactotroph adenoma development...
January 19, 2018: Oncotarget
Fang Huang, Wei Shao, Koh Fujinaga, B Matija Peterlin
Autoimmune regulator (AIRE) and nu-clear factor-kappa B (NF-κB) are transcription factors (TFs) that direct the expression of individual genes and gene clusters. Bromodomain-containing protein 4 (BRD4) is an epigenetic regulator that recognizes and binds to acetylated histones. BRD4 also has been reported to promote interactions between the positive elongation factor b (P-TEFb) and AIRE or P-TEFb and NF-κB subunit p65. Here, we report that AIRE and p65 bind to P-TEFb independently of BRD4. JQ1, a compound that disrupts interactions between BRD4 and acetylated proteins, does not decrease transcriptional activities of AIRE or p65...
February 20, 2018: Journal of Biological Chemistry
Afua A Akuffo, Aileen Y Alontaga, Rainer Metcalf, Matthew S Beatty, Andreas Becker, Jessica M McDaniel, Rebecca S Hesterberg, William E Goodheart, Steven Gunawan, Muhammad Ayaz, Yan Yang, Md Rezaul Karim, Morgan E Orobello, Kenyon Daniel, Wayne Guida, Jeffrey A Yoder, Anjali M Rajadhyaksha, Ernst Schonbrunn, Harshani R Lawrence, Nicholas J Lawrence, Pearlie K Epling-Burnette
Upon binding to thalidomide and other immunomodulatory drugs, the E3 ligase substrate receptor cereblon (CRBN) promotes proteasomal destruction by engaging the DDB1-CUL4A-Roc1-RBX1 E3-ubiquitin ligase in human cells but not in mouse cells suggesting that sequence variations in CRBN may cause its inactivation. Therapeutically, CRBN engagers have the potential for broad applications in cancer and immune therapy by specifically reducing protein expression through targeted ubiquitin-mediated degradation. To examine the effects of defined sequence changes on CRBNs activity, we performed a comprehensive study using complementary theoretical, biophysical, and biological assays aimed at understanding CRBNs non-primate sequence variations...
February 15, 2018: Journal of Biological Chemistry
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