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Alfonso Urbanucci, Stefan J Barfeld, Ville Kytölä, Harri M Itkonen, Ilsa M Coleman, Daniel Vodák, Liisa Sjöblom, Xia Sheng, Teemu Tolonen, Sarah Minner, Christoph Burdelski, Kati K Kivinummi, Annika Kohvakka, Steven Kregel, Mandeep Takhar, Mohammed Alshalalfa, Elai Davicioni, Nicholas Erho, Paul Lloyd, R Jeffrey Karnes, Ashley E Ross, Edward M Schaeffer, Donald J Vander Griend, Stefan Knapp, Eva Corey, Felix Y Feng, Peter S Nelson, Fahri Saatcioglu, Karen E Knudsen, Teuvo L J Tammela, Guido Sauter, Thorsten Schlomm, Matti Nykter, Tapio Visakorpi, Ian G Mills
Global changes in chromatin accessibility may drive cancer progression by reprogramming transcription factor (TF) binding. In addition, histone acetylation readers such as bromodomain-containing protein 4 (BRD4) have been shown to associate with these TFs and contribute to aggressive cancers including prostate cancer (PC). Here, we show that chromatin accessibility defines castration-resistant prostate cancer (CRPC). We show that the deregulation of androgen receptor (AR) expression is a driver of chromatin relaxation and that AR/androgen-regulated bromodomain-containing proteins (BRDs) mediate this effect...
June 6, 2017: Cell Reports
Jonathan T Lloyd, Karen C Glass
Bromodomain proteins function as epigenetic readers that recognize acetylated histone tails to facilitate the transcription of target genes. There are approximately 60 known human bromodomains, which are divided into 8 sub-families based on structural conservation. The bromodomain-containing proteins in family IV include 7 members (BRPF1, BRPF2, BRPF3, BRD7, BRD9, ATAD2 and ATAD2b). The bromodomains of each of these proteins recognize and bind acetyllysine residues on histone tails protruding from the nucleosome...
May 13, 2017: Journal of Cellular Physiology
Xue Guan, Zhi-Hong Zong, Shuo Chen, Xiu-Bo Sang, Dan-Dan Wu, Li-Li Wang, Yao Liu, Yang Zhao
OBJECTIVES: MicroRNA-372 has been shown to be associated with multiple tumors' development and progression, by regulating the expression of proteins involved in cell cycle and apoptosis. However, the specific mechanism and function of miR-372 in ovarian carcinoma are not clear. Our study explored the role of miR-372 in ovarian carcinoma cell cycle and proliferation. MATERIALS AND METHODS: MiR-372 expression was quantified in normal ovarian tissue, benign tumors, primary ovarian carcinomas and metastatic omentum by qRT-PCR...
August 15, 2017: Gene
Yawei Wang, Ye Hu, Gang Wu, Ye Yang, Yanqing Tang, Wanchuan Zhang, Kaiyu Wang, Yu Liu, Xin Wang, Tiemin Li
Long non-coding RNAs (lncRNAs) regulate oncogenesis by inducing methylation of CpG islands to silence target genes. Here we show that the lncRNA PCAT-14 is overexpressed in patients with hepatocellular carcinoma (HCC), and is associated with a poor prognosis after surgery. Our results demonstrate that PCAT-14 promotes proliferation, invasion, and cell cycle arrest in HCC cells. In addition, PCAT-14 inhibits miR-372 expression by inducing methylation of the miR-372 promoter. Simultaneously, miR-372 eliminates the effects of PCAT-14 on proliferation, invasion, and cell cycle in HCC cells...
May 23, 2017: Oncotarget
Dong Chen, Matthias Maruschke, Oliver Hakenberg, Wolfgang Zimmermann, Christian G Stief, Alexander Buchner
OBJECTIVE: To identify and validate novel prognostic marker genes in clear cell renal cell carcinoma (RCC) that are increasingly expressed during tumor progression. METHODS: Total RNA was isolated from normal renal tissue, primary G1 and G3 tumors, 14 samples each, and 32 metastases from RCC patients. Expression profiles were created using oligonucleotide microarrays. Significant gene expression differences (P < .05) were identified among normal kidney, primary tumor, and metastases...
January 6, 2017: Urology
Afsoon Taghavi, Mohammad Esmaeil Akbari, Mohammad Hashemi-Bahremani, Nahid Nafissi, Ahad Khalilnezhad, Seyed Mohammad Poorhosseini, Feyzollah Hashemi-Gorji, Vahid Reza Yassaee
Gene expression profiling has been suggested to predict breast cancer outcome. The prognostic value of the 8q22-24 position in breast cancer remains to be elucidated. The present study evaluated expression patterns of the genes located at this position in metastatic and non-metastatic breast cancer. A total of 85 patients with recurrent/metastatic (n=15) and non-metastatic (n=70) early-stage, estrogen receptor-positive and lymph node-negative breast tumors were included. In addition, 15 normal breast tissue samples were used as controls...
November 2016: Oncology Letters
Seong Joo Koo, Amaury E Fernández-Montalván, Volker Badock, Christopher J Ott, Simon J Holton, Oliver von Ahsen, Joern Toedling, Sarah Vittori, James E Bradner, Mátyás Gorjánácz
ATAD2 (ATPase family AAA domain-containing protein 2) is a chromatin regulator harboring an AAA+ ATPase domain and a bromodomain, previously proposed to function as an oncogenic transcription co-factor. Here we suggest that ATAD2 is also required for DNA replication. ATAD2 is co-expressed with genes involved in DNA replication in various cancer types and predominantly expressed in S phase cells where it localized on nascent chromatin (replication sites). Our extensive biochemical and cellular analyses revealed that ATAD2 is recruited to replication sites through a direct interaction with di-acetylated histone H4 at K5 and K12, indicative of newly synthesized histones during replication-coupled chromatin reassembly...
October 25, 2016: Oncotarget
S Hong, M Bi, S Chen, P Zhao, B Li, D Sun, J Tai
MicroRNAs (miRNAs) are small, non-coding RNAs that can serve as tumor suppressor genes or oncogenes in tumorigenesis. More and more evidence demonstrate that abnormal expression of miRNAs lead to the gastric carcinoma occurrence. In the present study, we revealed that the expression levels of miR-520f were significantly down-regulated in gastric carcinoma cells and clinical gastric carcinoma samples. Next, we demonstrated that introduction of miR-520f inhibited the growth of gastric carcinoma cells in vitro...
2016: Neoplasma
S Hong, M Bi, Z Yan, D Sun, L Ling, C Zhao
Colorectal cancer is one of the most common malignant tumors with a high rate of distant metastasis, postoperative recurrence and mortality. ATPase family AAA domain-containing protein 2 (ATAD2), a member of ATPase family, is highly expressed in various cancers, including colorectal cancer. However, whether ATAD2 plays a role in the migration and invasion of colorectal cancer cells remains unknown. In this study, we established ATAD2 knockdown in colorectal cancer cell lines by RNA interference and found that silencing of ATAD2 inhibited the migration and invasion ability of Caco-2 and SW-480 cells...
2016: Neoplasma
Paul Bamborough, Chun-Wa Chung, Emmanuel H Demont, Rebecca C Furze, Andrew J Bannister, Ka Hing Che, Hawa Diallo, Clement Douault, Paola Grandi, Tony Kouzarides, Anne-Marie Michon, Darren J Mitchell, Rab K Prinjha, Christina Rau, Samuel Robson, Robert J Sheppard, Richard Upton, Robert J Watson
ATAD2 is a cancer-associated protein whose bromodomain has been described as among the least druggable of that target class. Starting from a potent lead, permeability and selectivity were improved through a dual approach: 1) using CF2 as a sulfone bio-isostere to exploit the unique properties of fluorine, and 2) using 1,3-interactions to control the conformation of a piperidine ring. This resulted in the first reported low-nanomolar, selective and cell permeable chemical probe for ATAD2.
September 12, 2016: Angewandte Chemie
Sinisa Vukovic, Paul E Brennan, David J Huggins
The interaction between any two biological molecules must compete with their interaction with water molecules. This makes water the most important molecule in medicine, as it controls the interactions of every therapeutic with its target. A small molecule binding to a protein is able to recognize a unique binding site on a protein by displacing bound water molecules from specific hydration sites. Quantifying the interactions of these water molecules allows us to estimate the potential of the protein to bind a small molecule...
September 1, 2016: Journal of Physics. Condensed Matter: An Institute of Physics Journal
Mingming Hou, Rui Huang, Yanni Song, Di Feng, Yang Jiang, Ming Liu
OBJECTIVES: ATPase family AAA domain-containing 2 plays an important role in tumor progression including cell cycle, proliferation, apoptosis and chemoresistance. However, the expression of ATPase family AAA domain-containing 2 in colorectal cancer and its significance are still unclear. The aim of this study was to examine the expression of ATPase family AAA domain-containing 2 in colorectal cancer. METHODS: Immunohistochemistry was used to determine the expression of ATPase family AAA domain-containing 2 in 155 colorectal cancer and 30 matched adjacent noncancerous tissues...
March 2016: Japanese Journal of Clinical Oncology
F Anthony Romero, Alexander M Taylor, Terry D Crawford, Vickie Tsui, Alexandre Côté, Steven Magnuson
Bromodomains, small protein modules that recognize acetylated lysine on histones, play a significant role in the epigenome, where they function as "readers" that ultimately determine the functional outcome of the post-translational modification. Because the initial discovery of selective BET inhibitors have helped define the role of that protein family in oncology and inflammation, BET bromodomains have continued to garner the most attention of any other bromodomain. More recently, non-BET bromodomain inhibitors that are potent and selective have been disclosed for ATAD2, CBP, BRD7/9, BRPF, BRPF/TRIM24, CECR2, SMARCA4, and BAZ2A/B...
February 25, 2016: Journal of Medicinal Chemistry
M- J Zhang, C- Z Zhang, W- J Du, X- Z Yang, Z- P Chen
OBJECTIVE: ATPase family, AAA domain containing 2 (ATAD2) has been found overexpressed in various cancer types and correlated with malignant status and poor prognosis. However, little is known about the clinical significance of ATAD2 in gastric cancer patients. The aim of this study was to explore the clinical and prognostic significance of ATAD2 in gastric cancer. METHODS: The mRNA and protein levels expression of ATAD2 were detected in clinical tissue samples by qRT-PCR and immunohistochemistry, respectively...
August 2016: Clinical & Translational Oncology
Chih-Ping Chen, Ming-Huei Lin, Yi-Yung Chen, Schu-Rern Chern, Yen-Ni Chen, Peih-Shan Wu, Chen-Wen Pan, Meng-Shan Lee, Wayseen Wang
OBJECTIVE: The aim of this research was to present prenatal diagnosis of Langer-Giedion syndrome (LGS/TRPS type II) and Cornelia de Lange syndrome-4 (CDLS4). MATERIALS AND METHODS: A 36-year-old woman underwent amniocentesis at 17 weeks of gestation because of advanced maternal age. Conventional cytogenetic analysis of amniocentesis revealed an interstitial deletion of chromosome 8q or del(8)(q23.3q24.13). Level II prenatal ultrasound examination revealed craniofacial dysmorphism...
October 2015: Taiwanese Journal of Obstetrics & Gynecology
Yuichi Morozumi, Fayçal Boussouar, Minjia Tan, Apirat Chaikuad, Mahya Jamshidikia, Gozde Colak, Huang He, Litong Nie, Carlo Petosa, Maud de Dieuleveult, Sandrine Curtet, Anne-Laure Vitte, Clothilde Rabatel, Alexandra Debernardi, François-Loïc Cosset, Els Verhoeyen, Anouk Emadali, Norbert Schweifer, Davide Gianni, Marta Gut, Philippe Guardiola, Sophie Rousseaux, Matthieu Gérard, Stefan Knapp, Yingming Zhao, Saadi Khochbin
Although the conserved AAA ATPase and bromodomain factor, ATAD2, has been described as a transcriptional co-activator upregulated in many cancers, its function remains poorly understood. Here, using a combination of ChIP-seq, ChIP-proteomics, and RNA-seq experiments in embryonic stem cells where Atad2 is normally highly expressed, we found that Atad2 is an abundant nucleosome-bound protein present on active genes, associated with chromatin remodelling, DNA replication, and DNA repair factors. A structural analysis of its bromodomain and subsequent investigations demonstrate that histone acetylation guides ATAD2 to chromatin, resulting in an overall increase of chromatin accessibility and histone dynamics, which is required for the proper activity of the highly expressed gene fraction of the genome...
August 2016: Journal of Molecular Cell Biology
Camilla Krakstad, Ingvild L Tangen, Erling A Hoivik, Mari K Halle, Anna Berg, Henrica M Werner, Maria B Ræder, Kanthida Kusonmano, June X Zou, Anne M Øyan, Ingunn Stefansson, Jone Trovik, Karl-Henning Kalland, Hong-Wu Chen, Helga B Salvesen
We have explored the potential for clinical implementation of ATAD2 as a biomarker for aggressive endometrial cancer by investigating to what extent immunohistochemical (IHC) staining for ATAD2 is feasible, reflects clinical phenotype and molecular subgroups of endometrial carcinomas. Increased expression of the ATAD2 gene has been implicated in cancer development and progression in a number of tissues, but few studies have investigated ATAD2 expression using IHC. Here we show that high ATAD2 protein expression is significantly associated with established clinical-pathological variables for aggressive endometrial cancer, also in the subset of estrogen receptor α (ERα) positive tumors...
September 29, 2015: Oncotarget
Paul Bamborough, Chun-wa Chung, Rebecca C Furze, Paola Grandi, Anne-Marie Michon, Robert J Sheppard, Heather Barnett, Hawa Diallo, David P Dixon, Clement Douault, Emma J Jones, Bhumika Karamshi, Darren J Mitchell, Rab K Prinjha, Christina Rau, Robert J Watson, Thilo Werner, Emmanuel H Demont
ATAD2 is a bromodomain-containing protein whose overexpression is linked to poor outcomes in a number of different cancer types. To date, no potent and selective inhibitors of the bromodomain have been reported. This article describes the structure-based optimization of a series of naphthyridones from micromolar leads with no selectivity over the BET bromodomains to inhibitors with sub-100 nM ATAD2 potency and 100-fold BET selectivity.
August 13, 2015: Journal of Medicinal Chemistry
Emmanuel H Demont, Chun-wa Chung, Rebecca C Furze, Paola Grandi, Anne-Marie Michon, Chris Wellaway, Nathalie Barrett, Angela M Bridges, Peter D Craggs, Hawa Diallo, David P Dixon, Clement Douault, Amanda J Emmons, Emma J Jones, Bhumika V Karamshi, Kelly Locke, Darren J Mitchell, Bernadette H Mouzon, Rab K Prinjha, Andy D Roberts, Robert J Sheppard, Robert J Watson, Paul Bamborough
Overexpression of ATAD2 (ATPase family, AAA domain containing 2) has been linked to disease severity and progression in a wide range of cancers, and is implicated in the regulation of several drivers of cancer growth. Little is known of the dependence of these effects upon the ATAD2 bromodomain, which has been categorized as among the least tractable of its class. The absence of any potent, selective inhibitors limits clear understanding of the therapeutic potential of the bromodomain. Here, we describe the discovery of a hit from a fragment-based targeted array...
July 23, 2015: Journal of Medicinal Chemistry
Pan Shang, Fanling Meng, Yunduo Liu, Xiuwei Chen
This study aimed to explore the clinical significance of AAA+ (ATPases associated with various cellular activities) nuclear coregulator cancer-associated (ANCCA) protein expression in endometrial carcinoma (EC). Correlations of ANCCA expression with clinicopathological factors and prognosis of EC patients were analyzed. Expression of ANCCA was detected in EC from 207 patients along with corresponding normal endometrium specimens by immunohistochemistry. ANCCA immunoreactivity was overexpressed in EC cases compared with that in normal endometrium (P < 0...
June 2015: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
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