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Cancer AND BRD4

Tong Zhou, Luke Erber, Bing Liu, Yankun Gao, Hai-Bin Ruan, Yue Chen
Proline hydroxylation is a critical cellular mechanism regulating oxygen-response pathways in tumor initiation and progression. Yet, its substrate diversity and functions remain largely unknown. Here, we report a system-wide analysis to characterize proline hydroxylation substrates in cancer cells using an immunoaffinity-purification assisted proteomics strategy. We identified 562 sites from 272 proteins in HeLa cells. Bioinformatic analysis revealed that proline hydroxylation substrates are significantly enriched with mRNA processing and stress-response cellular pathways with canonical and diverse flanking sequence motifs...
October 13, 2016: Oncotarget
Emily J Faivre, Denise Wilcox, Xiaoyu Lin, Paul Hessler, Maricel Torrent, Wei He, Tamar Uziel, Daniel H Albert, Keith McDaniel, Warren Kati, Yu Shen
: Competitive inhibitors of acetyl-lysine binding to the bromodomains of the BET (bromodomain and extra terminal) family are being developed for the treatment of solid and hematologic malignancies. The function of BET family member BRD4 at enhancers/super-enhancers has been shown to sustain signal-dependent or pathogenic gene expression programs. Here the hypothesis was tested that the transcription factor drivers of castration-resistant prostate cancer (CRPC) clinical progression, including the Androgen Receptor (AR), are critically dependent on BRD4 and thus represent a sensitive solid tumor indication for the BET inhibitor ABBV-075...
October 5, 2016: Molecular Cancer Research: MCR
Terry D Crawford, F Anthony Romero, Kwong Wah Lai, Vickie Tsui, Alexander M Taylor, Gladys de Leon Boenig, Cameron L Noland, Jeremy Murray, Justin Ly, Edna F Choo, Thomas L Hunsaker, Emily W Chan, Mark Merchant, Samir Kharbanda, Karen E Gascoigne, Susan Kaufman, Maureen H Beresini, Jiangpeng Liao, Wenfeng Liu, Kevin X Chen, Zhongguo Chen, Andrew R Conery, Alexandre Côté, Hariharan Jayaram, Ying Jiang, James R Kiefer, Tracy Kleinheinz, Yingjie Li, Jonathan Maher, Eneida Pardo, Florence Poy, Kerry L Spillane, Fei Wang, Jian Wang, Xiaocang Wei, Zhaowu Xu, Zhongya Xu, Ivana Yen, Laura Zawadzke, Xiaoyu Zhu, Steven Bellon, Richard Cummings, Andrea G Cochran, Brian K Albrecht, Steven Magnuson
The single bromodomain of the closely related transcriptional regulators CBP/EP300 is a target of much recent interest in cancer and immune system regulation. A co-crystal structure of a ligand-efficient screening hit and the CBP bromodomain guided initial design targeting the LPF shelf, ZA loop, and acetylated lysine binding regions. Structure-activity relationship studies allowed us to identify a more potent analogue. Optimization of permeability and microsomal stability and subsequent improvement of mouse hepatocyte stability afforded 59 (GNE-272, TR-FRET IC50 = 0...
September 28, 2016: Journal of Medicinal Chemistry
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
Jennifer M Sahni, Sylvia S Gayle, Kristen L Weber-Bonk, Leslie Cuellar Vite, Jennifer L Yori, Bryan Webb, Erika K Ramos, Darcie D Seachrist, Melissa D Landis, Jenny C Chang, James E Bradner, Ruth A Keri
Bromodomain and extraterminal (BET) proteins are epigenetic "readers" that recognize acetylated histones and mark areas of the genome for transcription. BRD4, a BET family member protein, has been implicated in a number of types of cancer, and BET protein inhibitors (BETi) are efficacious in many preclinical cancer models. However, the drivers of response to BETi vary depending on tumor type, and little is known regarding the target genes conveying BETi activity in triple-negative breast cancer (TNBC). Here, we show that BETi repress growth of multiple in vitro and in vivo models of TNBC by inducing two terminal responses: apoptosis and senescence...
September 20, 2016: Journal of Biological Chemistry
Hengrui Zhu, Fee Bengsch, Nikolaos Svoronos, Melanie R Rutkowski, Benjamin G Bitler, Michael J Allegrezza, Yuhki Yokoyama, Andrew V Kossenkov, James E Bradner, Jose R Conejo-Garcia, Rugang Zhang
Restoration of anti-tumor immunity by blocking PD-L1 signaling through the use of antibodies has proven to be beneficial in cancer therapy. Here, we show that BET bromodomain inhibition suppresses PD-L1 expression and limits tumor progression in ovarian cancer. CD274 (encoding PD-L1) is a direct target of BRD4-mediated gene transcription. In mouse models, treatment with the BET inhibitor JQ1 significantly reduced PD-L1 expression on tumor cells and tumor-associated dendritic cells and macrophages, which correlated with an increase in the activity of anti-tumor cytotoxic T cells...
September 13, 2016: Cell Reports
Katharine E Dooley, Alix Warburton, Alison A McBride
UNLABELLED: In cancer cells associated with human papillomavirus (HPV) infections, the viral genome is very often found integrated into the cellular genome. The viral oncogenes E6 and E7 are transcribed from the viral promoter, and integration events that alter transcriptional regulation of this promoter contribute to carcinogenic progression. In this study, we detected highly enriched binding of the super-enhancer markers Brd4, MED1, and H3K27ac, visible as a prominent nuclear focus by immunofluorescence, at the tandemly integrated copies of HPV16 in cells of the cervical neoplasia cell line W12 subclone 20861...
2016: MBio
Hanlin Zeng, Jia Qu, Nan Jin, Jun Xu, Chenchu Lin, Yi Chen, Xinying Yang, Xiang He, Shuai Tang, Xiaojing Lan, Xiaotong Yang, Ziqi Chen, Min Huang, Jian Ding, Meiyu Geng
Histone deacetylase (HDAC) inhibitors have demonstrated clinical benefits in subtypes of hematological malignancies. However, the efficacy of HDAC inhibitors in solid tumors remains uncertain. This study takes breast cancer as a model to understand mechanisms accounting for limited response of HDAC inhibitors in solid tumors and to seek combination solutions. We discover that feedback activation of leukemia inhibitory factor receptor (LIFR) signaling in breast cancer limits the response to HDAC inhibition. Mechanistically, HDAC inhibition increases histone acetylation at the LIFR gene promoter, which recruits bromodomain protein BRD4, upregulates LIFR expression, and activates JAK1-STAT3 signaling...
September 12, 2016: Cancer Cell
Verónica García-Carpizo, Jacinto Sarmentero, Bomie Han, Osvaldo Graña, Sergio Ruiz-Llorente, David G Pisano, Manuel Serrano, Harold B Brooks, Robert M Campbell, Maria J Barrero
The histone methyltransferase NSD2/WHSC1/MMSET is overexpressed in a number of solid tumors but its contribution to the biology of these tumors is not well understood. Here, we describe that NSD2 contributes to the proliferation of a subset of lung cancer cell lines by supporting oncogenic RAS transcriptional responses. NSD2 knock down combined with MEK or BRD4 inhibitors causes co-operative inhibitory responses on cell growth. However, while MEK and BRD4 inhibitors converge in the downregulation of genes associated with cancer-acquired super-enhancers, NSD2 inhibition affects the expression of clusters of genes embedded in megabase-scale regions marked with H3K36me2 and that contribute to the RAS transcription program...
2016: Scientific Reports
Santosh Gupta, Jing Li, Gabor Kemeny, Rhonda L Bitting, Joshua Beaver, Jason Somarelli, Kathryn E Ware, Simon Gregory, Andrew J Armstrong
PURPOSE: Beyond enumeration, circulating tumor cells (CTCs) can provide genetic information from metastatic cancer that may facilitate a greater understanding of tumor biology and enable a precision medicine approach. EXPERIMENTAL DESIGN: CTCs and paired leukocytes from men with metastatic castration-resistant prostate cancer (mCRPC) were isolated from blood through red cell lysis, CD45 depletion, and flow sorting based on EpCAM/CD45 expression. We next performed whole genomic copy number analysis of CTCs and matched patient leukocytes (germline) using array-based comparative genomic hybridization (aCGH) from 16 men with mCRPC, including longitudinal and sequential CTCs aCGH analyses in the context of enzalutamide therapy...
September 6, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Seika Amemiya, Takao Yamaguchi, Taki Sakai, Yuichi Hashimoto, Tomomi Noguchi-Yachide
Bromodomains are epigenetic 'readers' of histone acetylation. The first potent bromodomain and extra-terminal domain (BET) inhibitors, (+)-JQ1 and I-BET762 (also known as GSK525762), were reported in 2010. Some BET inhibitors are already under clinical trial for the treatment of cancers, but so far, only a few chemical scaffolds are available. We have reported potent N(6)-benzoyladenine-based inhibitors of BRD4, a BET family member that serves as a key mediator of transcriptional elongation. Here we present an analysis of the structure-activity relationships of these inhibitors...
2016: Chemical & Pharmaceutical Bulletin
Yifei Yang, Leilei Zhao, Bin Xu, LingYun Yang, Jian Zhang, Huibin Zhang, Jinpei Zhou
BRD4 plays a key role in transcriptional regulation. Recent biological and pharmacological studies have demonstrated that bromodomain-containing protein 4 (BRD4) is a viable drug target for cancer treatment. In this study, we synthesized a series of dihydroquinoxalinone derivatives and evaluated their BRD4 inhibitory activities, obtaining compound 5i with IC50 value of 73nM of binding activity in BRD4(1) and 258nM of cellular activity in MV-4-11 cancer cell lines. Docking studies were performed to explain the structure-activity relationship...
October 2016: Bioorganic Chemistry
Haifeng Qiu, Jing Li, Leslie H Clark, Amanda L Jackson, Lu Zhang, Hui Guo, Joshua E Kilgore, Paola A Gehrig, Chunxiao Zhou, Victoria L Bae-Jump
Overexpression of c-Myc is associated with worse outcomes in endometrial cancer, indicating that c-Myc may be a promising target for endometrial cancer therapy. A novel small molecule, JQ1, has been shown to block BRD4 resulting in inhibition of c-Myc expression and tumor growth. Thus, we investigated whether JQ1 can inhibit endometrial cancer growth in cell culture and xenograft models. In PTEN-positive endometrial cancer cells, JQ1 significantly suppressed cell proliferation via induction of G1 phase arrest and apoptosis in a dose-dependent manner, accompanied by a sharp decline in cyclin D1 and CDK4 protein expression...
August 26, 2016: Oncotarget
Ahmed F Abdel-Magid
No abstract text is available yet for this article.
August 11, 2016: ACS Medicinal Chemistry Letters
Yuki Kagoya, Munehide Nakatsugawa, Yuki Yamashita, Toshiki Ochi, Tingxi Guo, Mark Anczurowski, Kayoko Saso, Marcus O Butler, Cheryl H Arrowsmith, Naoto Hirano
Adoptive immunotherapy is a potentially curative therapeutic approach for patients with advanced cancer. However, the in vitro expansion of antitumor T cells prior to infusion inevitably incurs differentiation towards effector T cells and impairs persistence following adoptive transfer. Epigenetic profiles regulate gene expression of key transcription factors over the course of immune cell differentiation, proliferation, and function. Using comprehensive screening of chemical probes with defined epigenetic targets, we found that JQ1, an inhibitor of bromodomain and extra-terminal motif (BET) proteins, maintained CD8+ T cells with functional properties of stem cell-like and central memory T cells...
September 1, 2016: Journal of Clinical Investigation
Michelle Hussong, Christian Kaehler, Martin Kerick, Christina Grimm, Alexandra Franz, Bernd Timmermann, Franziska Welzel, Jörg Isensee, Tim Hucho, Sylvia Krobitsch, Michal R Schweiger
The cellular response to heat stress is an ancient and evolutionarily highly conserved defence mechanism characterised by the transcriptional up-regulation of cyto-protective genes and a partial inhibition of splicing. These features closely resemble the proteotoxic stress response during tumor development. The bromodomain protein BRD4 has been identified as an integral member of the oxidative stress as well as of the inflammatory response, mainly due to its role in the transcriptional regulation process. In addition, there are also several lines of evidence implicating BRD4 in the splicing process...
August 17, 2016: Nucleic Acids Research
Chengyue Zhang, Zheng-Yuan Su, Ling Wang, Limin Shu, Yuqing Yang, Yue Guo, Douglas Pung, Chas Bountra, Ah-Ng Kong
The neoplastic transformation of cells and inflammation are processes that contribute to tumor initiation. Recently, emerging evidence has suggested that epigenetic alterations are also implicated in the early stages of carcinogenesis. Therefore, potent small molecules targeting epigenetic regulators have been developed as novel cancer therapeutic and preventive strategies. Bromodomain and extraterminal domain (BET) proteins are epigenetic readers that play key roles at the interface between chromatin modification and transcriptional regulation...
October 1, 2016: Biochemical Pharmacology
Nicole G Chau, Shelley Hurwitz, Chelsey M Mitchell, Alexandra Aserlind, Noam Grunfeld, Leah Kaplan, Peter Hsi, Daniel E Bauer, Christopher S Lathan, Carlos Rodriguez-Galindo, Roy B Tishler, Robert I Haddad, Stephen E Sallan, James E Bradner, Christopher A French
BACKGROUND: NUT midline carcinoma is a rare and aggressive genetically characterized subtype of squamous cell carcinoma frequently arising from the head and neck. The characteristics and optimal management of head and neck NUT midline carcinoma (HNNMC) are unclear. METHODS: A retrospective review of all known cases of HNNMC in the International NUT Midline Carcinoma Registry as of December 31, 2014, was performed. Forty-eight consecutive patients were treated from 1993 to 2014, and clinicopathologic variables and outcomes for 40 patients were available for analyses; they composed the largest HNNMC cohort studied to date...
August 10, 2016: Cancer
Utkarsh Raj, Himansu Kumar, Pritish Kumar Varadwaj
Bromodomains (BRDs) are the epigenetic proteins responsible for transcriptional regulation through its interaction with methylated or acetylated histone residues. The lysine residues of Bromodomain-1 (BD1) of Brd4 undergo ε-N-Acetylation posttranslational modifications to control transcription of genes. Due to its role in diverse cellular functions, Brd4 of bromodomain family, was considered as a prominent target for many diseases such as cancer, obesity, kidney disease, lung fibrosis, inflammatory diseases, etc...
August 5, 2016: Journal of Biomolecular Structure & Dynamics
Shwu-Yuan Wu, Dawn Sijin Nin, A-Young Lee, Scott Simanski, Thomas Kodadek, Cheng-Ming Chiang
Post-translational modification can modulate protein conformation and alter binding partner recruitment within gene regulatory regions. Here, we report that bromodomain-containing protein 4 (BRD4), a transcription co-factor and chromatin regulator, uses a phosphorylation-induced switch mechanism to recruit E2 protein encoded by cancer-associated human papillomavirus (HPV) to viral early gene and cellular matrix metalloproteinase-9 (MMP-9) promoters. Enhanced MMP-9 expression, induced upon keratinocyte differentiation, occurs via BRD4-dependent recruitment of active AP-1 and NF-κB to their target sequences...
August 9, 2016: Cell Reports
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