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Cancer AND BRD4

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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/29296220/sequencing-of-lynch-syndrome-tumors-reveals-the-importance-of-epigenetic-alterations
#2
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/29196562/the-role-of-bromodomain-and-extraterminal-motif-bet-proteins-in-chromatin-structure
#3
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
https://www.readbyqxmd.com/read/29189147/disrupting-acetyl-lysine-interactions-recent-advance-in-the-development-of-bet-inhibitors
#4
Fa Zhang, Shutao Ma
BACKGROUND: Histone acetylation is an essential way of post-translational modification (PTM) and a significant component of epigenetic regulation that is mediated by Bromodomain-containing protein (BRD). In recent years, many researchers have found that a variety of malignancy, inflammatory and other diseases occurrence and development are associated with BRD4 expression disorders or dysfunction. Meanwhile, many the bromodomain inhibitors of the bromodomains and extra-terminal (BET) family is reported in many papers...
November 29, 2017: Current Drug Targets
https://www.readbyqxmd.com/read/29187284/jq1-a-bet-inhibitor-controls-tlr4-induced-il-10-production-in-regulatory-b-cells-by-brd4-nf-%C3%AE%C2%BAb-axis
#5
Min Bum Lee, JunHo Lee, Seong Hwi Hong, Jueng Soo You, Seung Taek Nam, Hyun Woo Kim, Young Hwan Park, Dajeong Lee, Keun Young Min, Yeong-Min Park, Young Mi Kim, Hyuk Soon Kim, Wahn Soo Choi
Regulatory B cells, also well-known as IL-10-producing B cells, play a role in the suppression of inflammatory responses. However, the epigenetic modulation of regulatory B cells is largely unknown. Recent studies showed that the bromodomain and extra-terminal domain (BET) protein inhibitor JQ1 controls the expression of various genes involving cell proliferation and cell cycle. However, the role of BET proteins on development of regulatory B cells is not reported. In this study, JQ1 potently suppressed IL-10 expression and secretion in murine splenic and peritoneal B cells...
November 29, 2017: BMB Reports
https://www.readbyqxmd.com/read/29180474/vitamin-c-sensitizes-melanoma-to-bet-inhibitors
#6
Gaofeng Wang, Sushmita Mustafi, Vladimir Camarena, Claude-Henry Volmar, Tyler C Huff, David W Sant, Shaun P Brothers, Zhao-Jun Liu, Claes Wahlestedt
Bromodomain and extra-terminal inhibitors (BETi) are promising cancer therapies, yet prominent side effects of BETi at effective doses have been reported in Phase I clinical trials. Here we screened a panel of small molecules targeting epigenetic modulators against human metastatic melanoma cells. Cells were pretreated with or without ascorbate (vitamin C), which promotes DNA demethylation and subsequently changes the sensitivity to drugs. Top hits were structurally unrelated BETi including JQ1, I-BET151, CPI-203, and BI-2536...
November 27, 2017: Cancer Research
https://www.readbyqxmd.com/read/29176719/structural-mechanism-of-the-oxygenase-jmjd6-recognition-by-the-extraterminal-et-domain-of-brd4
#7
Tsuyoshi Konuma, Di Yu, Chengcheng Zhao, Ying Ju, Rajal Sharma, Chunyan Ren, Qiang Zhang, Ming-Ming Zhou, Lei Zeng
Jumonji domain-containing protein 6 (JMJD6) is a member of the Jumonji C family of Fe(II) and 2-oxoglutarate (2OG) dependent oxygenases. It possesses unique bi-functional oxygenase activities, acting as both an arginine demethylase and a lysyl-hydroxylase. JMJD6 has been reported to be over-expressed in oral, breast, lung, and colon cancers and plays important roles in regulation of transcription through interactions with transcription regulator BRD4, histones, U2AF65, Luc7L3, and SRSF11. Here, we report a structural mechanism revealed by NMR of JMJD6 recognition by the extraterminal (ET) domain of BRD4 in that a JMJD6 peptide (Lys84-Asn96) adapts an α-helix when bound to the ET domain...
November 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29172540/discovery-of-a-small-molecule-bromodomain-containing-protein-4-brd4-inhibitor-that-induces-amp-activated-protein-kinase-modulated-autophagy-associated-cell-death-in-breast-cancer
#8
Liang Ouyang, Lan Zhang, Jie Liu, Leilei Fu, Dahong Yao, Yuqian Zhao, Shouyue Zhang, Guan Wang, Gu He, Bo Liu
Upon the basis of The Cancer Genome Atlas (TCGA) data set, we identified that several autophagy-related proteins such as AMP-activated protein kinase (AMPK) were remarkably downregulated in breast cancer. Combined with coimmunoprecipitation assay, we demonstrated that BRD4 might interact with AMPK. After analyses of the pharmacophore and WPF interaction optimization, we designed a small-molecule inhibitor of BRD4, 9f (FL-411) which was validated by cocrystal structure with BD1 of BRD4. Subsequently, 9f was discovered to induce ATG5-dependent autophagy-associated cell death (ACD) by blocking BRD4-AMPK interaction and thus activating AMPK-mTOR-ULK1-modulated autophagic pathway in breast cancer cells...
December 7, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29170024/exploiting-a-water-network-to-achieve-enthalpy-driven-bromodomain-selective-bet-inhibitors
#9
William R Shadrick, Peter J Slavish, Sergio C Chai, Brett Waddell, Michele Connelly, Jonathan A Low, Cynthia Tallant, Brandon M Young, Nagakumar Bharatham, Stefan Knapp, Vincent A Boyd, Marie Morfouace, Martine F Roussel, Taosheng Chen, Richard E Lee, R Kiplin Guy, Anang A Shelat, Philip M Potter
Within the last decade, the Bromodomain and Extra-Terminal domain family (BET) of proteins have emerged as promising drug targets in diverse clinical indications including oncology, auto-immune disease, heart failure, and male contraception. The BET family consists of four isoforms (BRD2, BRD3, BRD4, and BRDT/BRDT6) which are distinguished by the presence of two tandem bromodomains (BD1 and BD2) that independently recognize acetylated-lysine (KAc) residues and appear to have distinct biological roles. BET BD1 and BD2 bromodomains differ at five positions near the substrate binding pocket: the variation in the ZA channel induces different water networks nearby...
November 4, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/29167426/epigenetic-targeting-of-bromodomain-protein-brd4-counteracts-cancer-cachexia-and-prolongs-survival
#10
Marco Segatto, Raffaella Fittipaldi, Fabrizio Pin, Roberta Sartori, Kyung Dae Ko, Hossein Zare, Claudio Fenizia, Gianpietro Zanchettin, Elisa Sefora Pierobon, Shinji Hatakeyama, Cosimo Sperti, Stefano Merigliano, Marco Sandri, Panagis Filippakopoulos, Paola Costelli, Vittorio Sartorelli, Giuseppina Caretti
Cancer cachexia is a devastating metabolic syndrome characterized by systemic inflammation and massive muscle and adipose tissue wasting. Although it is responsible for approximately one-third of cancer deaths, no effective therapies are available and the underlying mechanisms have not been fully elucidated. We previously identified the bromodomain and extra-terminal domain (BET) protein BRD4 as an epigenetic regulator of muscle mass. Here we show that the pan-BET inhibitor (+)-JQ1 protects tumor-bearing mice from body weight loss and muscle and adipose tissue wasting...
November 22, 2017: Nature Communications
https://www.readbyqxmd.com/read/29133261/dual-inhibition-of-brd4-and-pi3k-by-sf2523-suppresses-human-prostate-cancer-cell-growth-in-vitro-and-in-vivo
#11
Gang Shen, Minjun Jiang, Jinxian Pu
Bromodomain-containing protein 4 (BRD4) and phosphatidylinositol 3-kinase (PI3K) are both key oncogenic proteins in human prostate cancer. In the current study, we examined the anti-prostate cancer cell activity by SF2523, a BRD4 and PI3K dual inhibitor. We showed that SF2523 potently inhibited survival and proliferation of the primary human prostate cancer cells. SF2523 induced profound apoptosis activation in prostate cancer cells. The dual inhibitor was yet non-cytotoxic to the prostate epithelial cells...
November 10, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29108467/spop-mediated-degradation-of-brd4-dictates-cellular-sensitivity-to-bet-inhibitors
#12
Xiangpeng Dai, Zhiwei Wang, Wenyi Wei
Bromodomain and extra-terminal (BET) proteins are frequently overexpressed in various human cancers, therefore have been clinically pursed as attractive therapeutic anti-cancer targets. However, relatively little is known about the mechanism(s) underlying aberrant BET overexpression in human cancers. Recently, we reported that prostate cancer-derived SPOP mutants fail to interact with and promote BRD4 degradation, leading to accumulation of BRD4 in prostate cancer cells. As a result, prostate cancer cells harboring SPOP mutations are more resistant to BET inhibitors...
November 6, 2017: Cell Cycle
https://www.readbyqxmd.com/read/29103140/synthesis-and-biological-evaluation-of-indazole-4-7-dione-derivatives-as-novel-brd4-inhibitors
#13
Minjin Yoo, Miyoun Yoo, Ji Eun Kim, Heung Kyoung Lee, Chong Ock Lee, Chi Hoon Park, Kwan-Young Jung
Bromodomain-containing protein 4 (BRD4) is known to regulate the expression of c-Myc to control the proliferation of cancer cells. Therefore, development of small-molecule inhibitors targeting the bromodomain has been widely studied. However, some clinical trials on BRD4 inhibitors have shown its drawbacks such as toxicity including the loss of organ weight. Here, we report the development of the novel and promising scaffold, 1H-indazol-4,7-dione, as a bromodomain inhibitor and synthesized derivatives for the inhibition of binding of bromodomain to acetylated histone peptide...
November 4, 2017: Archives of Pharmacal Research
https://www.readbyqxmd.com/read/29079177/sinonasal-nut-carcinoma-clinicopathological-and-cytogenetic-analysis-with-autopsy-findings
#14
Hiroshi Minato, Eriko Kobayashi, Satoko Nakada, Nozomu Kurose, Mio Tanaka, Yukichi Tanaka, Shioto Suzuki, Fumihiko Tanioka, Yutaka Saikawa, Takaki Miwa, Takayuki Nojima
Nuclear protein in testis (NUT) carcinoma is a rare malignant neoplasm with an undifferentiated morphology. Its diagnosis is often difficult, especially as the sinonasal tract gives rise to many tumors with undifferentiated morphologies. Not many cases of sinonasal NUT carcinomas have been reported, and its clinicopathological features have not been sufficiently clarified. In this study, we performed a clinicopathological study of 4 patients with sinonasal NUT carcinoma, including wide-ranging immunohistochemical tests and cytogenetic analyses using fluorescence in situ hybridization and DNA sequencing...
October 24, 2017: Human Pathology
https://www.readbyqxmd.com/read/29075615/pharmacologic-targeting-of-chromatin-modulators-as-therapeutics-of-acute-myeloid-leukemia
#15
REVIEW
Rui Lu, Gang Greg Wang
Acute myeloid leukemia (AML), a common hematological cancer of myeloid lineage cells, generally exhibits poor prognosis in the clinic and demands new treatment options. Recently, direct sequencing of samples from human AMLs and pre-leukemic diseases has unveiled their mutational landscapes and significantly advanced the molecular understanding of AML pathogenesis. The newly identified recurrent mutations frequently "hit" genes encoding epigenetic modulators, a wide range of chromatin-modifying enzymes and regulatory factors involved in gene expression regulation, supporting aberration of chromatin structure and epigenetic modification as a main oncogenic mechanism and cancer-initiating event...
2017: Frontiers in Oncology
https://www.readbyqxmd.com/read/28986391/altered-hydroxymethylation-is-seen-at-regulatory-regions-in-pancreatic-cancer-and-regulates-oncogenic-pathways
#16
Sanchari Bhattacharyya, Kith Pradhan, Nathaniel Campbell, Jozef Mazdo, Aparna Vasantkumar, Shahina Maqbool, Tushar D Bhagat, Sonal Gupta, Masako Suzuki, Yiting Yu, John M Greally, Ulrich Steidl, James Bradner, Meelad Dawlaty, Lucy Godley, Anirban Maitra, Amit Verma
Transcriptional deregulation of oncogenic pathways is a hallmark of cancer and can be due to epigenetic alterations. 5-Hydroxymethylcytosine (5-hmC) is an epigenetic modification that has not been studied in pancreatic cancer. Genome-wide analysis of 5-hmC-enriched loci with hmC-seal was conducted in a cohort of low-passage pancreatic cancer cell lines, primary patient-derived xenografts, and pancreatic controls and revealed strikingly altered patterns in neoplastic tissues. Differentially hydroxymethylated regions preferentially affected known regulatory regions of the genome, specifically overlapping with known H3K4me1 enhancers...
November 2017: Genome Research
https://www.readbyqxmd.com/read/28983974/molecular-design-of-stat3-derived-peptide-selectivity-between-bet-proteins-brd2-and-brd4-in-ovarian-cancer
#17
Lixia Zhu, Xi Ding
Stat3 signaling has been recognized as a potential therapeutic target of human ovarian cancer. The signaling is transducted through the peptide-medicated interaction of Stat3 with BET family members Brd2 and Brd4 -- 2 highly homologous proteins involved in differential downstream pathways. Here, we reported a successful design of peptide selectivity between the Brd2 and Brd4. The design resulted in 3 linear peptides SMSLQCXYLGVA, QSKVLTXSYWGA, and RQCNLGXLYMNY with high or moderate selectivity for Brd2 over Brd4 (S = 3...
October 6, 2017: Journal of Molecular Recognition: JMR
https://www.readbyqxmd.com/read/28981843/runx2-expression-in-thyroid-and-breast-cancer-requires-the-cooperation-of-three-non-redundant-enhancers-under-the-control-of-brd4-and-c-jun
#18
Valentina Sancisi, Gloria Manzotti, Mila Gugnoni, Teresa Rossi, Greta Gandolfi, Giulia Gobbi, Federica Torricelli, Francesca Catellani, Italo Faria do Valle, Daniel Remondini, Gastone Castellani, Moira Ragazzi, Simonetta Piana, Alessia Ciarrocchi
Aberrant reactivation of embryonic pathways is a common feature of cancer. RUNX2 is a transcription factor crucial during embryogenesis that is aberrantly reactivated in many tumors, including thyroid and breast cancer, where it promotes aggressiveness and metastatic spreading. Currently, the mechanisms driving RUNX2 expression in cancer are still largely unknown. Here we showed that RUNX2 transcription in thyroid and breast cancer requires the cooperation of three distantly located enhancers (ENHs) brought together by chromatin three-dimensional looping...
September 7, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28967088/uncommon-somatic-mutations-in-metastatic-nut-midline-carcinoma
#19
Stefano Cavalieri, Anastasios Stathis, Alessandra Fabbri, Angelica Sonzogni, Federica Perrone, Elena Tamborini, Giuseppe Pelosi, Filippo de Braud, Marco Platania
INTRODUCTION: NUT midline carcinoma (NMC) is a rare and aggressive epithelial cancer arising from median organs. It is driven by chromosomal translocation t(15;19) involving the rearrangement of NUT (nuclear protein in testis) and BRD4 (bromodomain 4) genes leading to fusion oncoprotein BRD4-NUT. CASE PRESENTATION: We report the case of a woman who was previously treated with induction chemotherapy, surgery, radiotherapy and adjuvant trastuzumab for HER-2 positive invasive ductal carcinoma of the breast...
November 15, 2017: Tumori
https://www.readbyqxmd.com/read/28949335/the-bet-brd-inhibitor-jq1-improves-brain-plasticity-in-wt-and-app-mice
#20
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
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