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EWS-FLI1 DNA damage

Monica Mangoni, Mariangela Sottili, Giulia Salvatore, Domenico Campanacci, Guido Scoccianti, Giovanni Beltrami, Camilla Delli Paoli, Luca Dominici, Virginia Maragna, Emanuela Olmetto, Icro Meattini, Isacco Desideri, Pierluigi Bonomo, Daniela Greto, Lorenzo Livi
BACKGROUND: Poly(ADP-ribose) polymerases (PARP) are a large family of enzymes involved in several cellular processes, including DNA single-strand break repair via the base-excision repair pathway. PARP inhibitors exert antitumor activity by both catalytic PARP inhibition and PARP-DNA trapping, moreover PARP inhibition represents a potential synthetic lethal approach against cancers with specific DNA-repair defects. Soft tissue sarcoma (STSs) are a heterogeneous group of mesenchymal tumors with locally destructive growth, high risk of recurrence and distant metastasis...
March 26, 2018: La Radiologia Medica
Aparna Gorthi, July Carolina Romero, Eva Loranc, Lin Cao, Liesl A Lawrence, Elicia Goodale, Amanda Balboni Iniguez, Xavier Bernard, V Pragathi Masamsetti, Sydney Roston, Elizabeth R Lawlor, Jeffrey A Toretsky, Kimberly Stegmaier, Stephen L Lessnick, Yidong Chen, Alexander J R Bishop
Ewing sarcoma is an aggressive paediatric cancer of the bone and soft tissue. It results from a chromosomal translocation, predominantly t(11;22)(q24:q12), that fuses the N-terminal transactivation domain of the constitutively expressed EWSR1 protein with the C-terminal DNA binding domain of the rarely expressed FLI1 protein. Ewing sarcoma is highly sensitive to genotoxic agents such as etoposide, but the underlying molecular basis of this sensitivity is unclear. Here we show that Ewing sarcoma cells display alterations in regulation of damage-induced transcription, accumulation of R-loops and increased replication stress...
March 15, 2018: Nature
Maria Nieto-Soler, Isabel Morgado-Palacin, Vanesa Lafarga, Emilio Lecona, Matilde Murga, Elsa Callen, Daniel Azorin, Javier Alonso, Andres J Lopez-Contreras, Andre Nussenzweig, Oscar Fernandez-Capetillo
Ewing sarcomas (ES) are pediatric bone tumors that arise from a driver translocation, most frequently EWS/FLI1. Current ES treatment involves DNA damaging agents, yet the basis for the sensitivity to these therapies remains unknown. Oncogene-induced replication stress (RS) is a known source of endogenous DNA damage in cancer, which is suppressed by ATR and CHK1 kinases. We here show that ES suffer from high endogenous levels of RS, rendering them particularly dependent on the ATR pathway. Accordingly, two independent ATR inhibitors show in vitro toxicity in ES cell lines as well as in vivo efficacy in ES xenografts as single agents...
September 13, 2016: Oncotarget
Kelli L Goss, David J Gordon
There is a critical need in cancer therapeutics to identify targeted therapies that will improve outcomes and decrease toxicities compared to conventional, cytotoxic chemotherapy. Ewing sarcoma is a highly aggressive bone and soft tissue cancer that is caused by the EWS-FLI1 fusion protein. Although EWS-FLI1 is specific for cancer cells, and required for tumorigenesis, directly targeting this transcription factor has proven challenging. Consequently, targeting unique dependencies or key downstream mediators of EWS-FLI1 represent important alternative strategies...
September 27, 2016: Oncotarget
Marco Fidaleo, Francesca Svetoni, Elisabetta Volpe, Belén Miñana, Daniela Caporossi, Maria Paola Paronetto
Alternative splicing plays a key role in the DNA damage response and in cancer. Ewing Sarcomas (ES) are aggressive tumors caused by different chromosomal translocations that yield in-frame fusion proteins driving transformation. RNA profiling reveals genes differentially regulated by UV light irradiation in two ES cell lines exhibiting different sensitivity to genotoxic stress. In particular, irradiation induces a new isoform of the RNA helicase DHX9 in the more sensitive SK-N-MC cells, which is targeted to nonsense-mediated decay (NMD), causing its downregulation...
October 13, 2015: Oncotarget
Ana Teresa Amaral, Cecilia Garofalo, Roberta Frapolli, Maria Cristina Manara, Caterina Mancarella, Sarah Uboldi, Silvana Di Giandomenico, Jose Luis Ordóñez, Victoria Sevillano, Roberta Malaguarnera, Piero Picci, A Bass Hassan, Enrique De Alava, Maurizio D'Incalci, Katia Scotlandi
PURPOSE: Goal of this study was to identify mechanisms that limit efficacy of trabectedin (ET-743, Yondelis) in Ewing sarcoma (EWS), so as to develop a clinical applicable combination therapy. EXPERIMENTAL DESIGN: By chromatin immunoprecipitation, we analyzed EWS-FLI1 binding to the promoters of several target genes, such as TGFβR2, CD99, insulin-like growth factor receptor 1 (IGF1R), and IGF1, both in vitro and in xenografts treated with trabectedin or doxorubicin...
March 15, 2015: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Heinrich Kovar
INTRODUCTION: Ewing sarcoma (ES) represents the paradigm of an aberrant E-twenty-six (ETS) oncogene-driven cancer. It is characterized by specific rearrangements of one of five alternative ETS family member genes with EWSR1. There is experimental evidence that the resulting fusion proteins act as aberrant transcription factors driving ES pathogenesis. The transcriptional gene regulatory network driven by EWS-ETS proteins provides the oncogenic engine to the tumor. Therefore, EWS-ETS and their downstream machinery are considered ideal tumor-specific therapeutic targets...
November 2014: Expert Opinion on Therapeutic Targets
Maria Paola Paronetto, Isabella Bernardis, Elisabetta Volpe, Elias Bechara, Endre Sebestyén, Eduardo Eyras, Juan Valcárcel
The Ewing sarcoma protein EWS is an RNA and DNA binding protein implicated in transcription, pre-mRNA splicing, and DNA damage response. Using CLIP-seq, we identified EWS RNA binding sites in exonic regions near 5' splice sites. A prominent target was exon 6 of the FAS/CD95 receptor, which is alternatively spliced to generate isoforms with opposing activities in programmed cell death. Depletion and overexpression experiments showed that EWS promotes exon 6 inclusion and consequently the synthesis of the proapoptotic FAS/CD95 isoform, whereas an EWS-FLI1 fusion protein characteristic of Ewing sarcomas shows decreased activity...
May 22, 2014: Cell Reports
Patrick J Grohar, Laure E Segars, Choh Yeung, Yves Pommier, Maurizio D'Incalci, Arnulfo Mendoza, Lee J Helman
PURPOSE: The goal of this study is to optimize the activity of trabectedin for Ewing sarcoma by developing a molecularly targeted combination therapy. EXPERIMENTAL DESIGN: We have recently shown that trabectedin interferes with the activity of EWS-FLI1 in Ewing sarcoma cells. In this report, we build on this work to develop a trabectedin-based combination therapy with improved EWS-FLI1 suppression that also targets the drug-associated DNA damage to Ewing sarcoma cells...
March 1, 2014: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Maria Paola Paronetto
The Ewing sarcoma protein (EWS) is a well-known player in cancer biology for the specific translocations occurring in sarcomas. The EWS-FLI1 gene fusion is the prototypical translocation that encodes the aberrant, chimeric transcription factor, which is a landmark of Ewing tumors. In all described Ewing sarcoma oncogenes, the EWS RNA binding domains are completely missing; thus RNA binding properties are not retained in the hybrid proteins. However, it is currently unknown whether the absence of EWS function in RNA metabolism plays a role in oncogenic transformation or if EWS plays a role by itself in cancer development besides its contribution to the translocation...
2013: International Journal of Cell Biology
Hae-June Lee, Changhwan Yoon, Benjamin Schmidt, Do Joong Park, Alexia Y Zhang, Hayriye V Erkizan, Jeffrey A Toretsky, David G Kirsch, Sam S Yoon
Ewing sarcomas (ES) harbor a chromosomal translocation that fuses the EWS gene to an ETS transcription factor, most commonly Friend leukemia integration 1 (FLI1). The EWS-FLI1 fusion protein acts in a positive feedback loop to maintain the expression of PARP-1, which is involved in repair of DNA damage. Here, we examine the effects of PARP-1 inhibition and radiation therapy on Ewing sarcomas. In proliferation assays, the Ewing sarcoma cell lines RD-ES and SK-N-MC were much more sensitive than non-Ewing sarcoma cell lines to the PARP-1 inhibitor olaparib (Ola; IC50 0...
November 2013: Molecular Cancer Therapeutics
Tyler P Robin, Anna Smith, Erin McKinsey, Lisa Reaves, Paul Jedlicka, Heide L Ford
Ewing sarcoma is an aggressive pediatric cancer of the bone and soft tissue, in which patients whose tumors have a poor histologic response to initial chemotherapy have a poor overall prognosis. Therefore, it is important to identify molecules involved in resistance to chemotherapy. Herein, we show that the DNA repair protein and transcriptional cofactor, EYA3, is highly expressed in Ewing sarcoma tumor samples and cell lines compared with mesenchymal stem cells, the presumed cell-of-origin of Ewing sarcoma, and that it is regulated by the EWS/FLI1 fusion protein transcription factor...
August 2012: Molecular Cancer Research: MCR
J Chad Brenner, Felix Y Feng, Sumin Han, Sonam Patel, Siddharth V Goyal, Laura M Bou-Maroun, Meilan Liu, Robert Lonigro, John R Prensner, Scott A Tomlins, Arul M Chinnaiyan
Ewing's sarcoma family of tumors (ESFT) refers to aggressive malignancies which frequently harbor characteristic EWS-FLI1 or EWS-ERG genomic fusions. Here, we report that these fusion products interact with the DNA damage response protein and transcriptional coregulator PARP-1. ESFT cells, primary tumor xenografts, and tumor metastases were all highly sensitive to PARP1 inhibition. Addition of a PARP1 inhibitor to the second-line chemotherapeutic agent temozolamide resulted in complete responses of all treated tumors in an EWS-FLI1-driven mouse xenograft model of ESFT...
April 1, 2012: Cancer Research
Yan Li, Xu Li, Guangyu Fan, Jun-Ichi Fukushi, Yoshihiro Matsumoto, Yukihide Iwamoto, Yue Zhu
The chromosomal translocation t(11;22)(q24;q12) yields the EWS-Fli1 fusion gene, which contributes to the development of Ewing Family Tumors (EFTs). Previous studies have shown the ability of EWS-Fli1 chimeric protein to silence p53 activity. Here we demonstrate that the introduction of EWS-Fli1 significantly inhibited p300-mediated acetylation of p53 at Lys-382 and depletion of EWS-Fli1 protein by small interfering RNAs (siRNA) in EFTs cells facilitated it in response to DNA damage. Furthermore, the deacetylation of p53 by EWS-Fli1 suppressed its transcriptional activity and enhanced mdm2-mediated p53 degradation...
July 1, 2012: Cancer Letters
Patrick J Grohar, Girma M Woldemichael, Laurie B Griffin, Arnulfo Mendoza, Qing-Rong Chen, Choh Yeung, Duane G Currier, Sean Davis, Chand Khanna, Javed Khan, James B McMahon, Lee J Helman
BACKGROUND: Chromosomal translocations generating oncogenic transcription factors are the hallmark of a variety of tumors, including many sarcomas. Ewing sarcoma family of tumors (ESFTs) are characterized by the t(11;22)(q24;q12) translocation that generates the Ewing sarcoma breakpoint region 1 and Friend leukemia virus integration 1 (EWS-FLI1) fusion transcription factor responsible for the highly malignant phenotype of this tumor. Although continued expression of EWS-FLI1 is believed to be critical for ESFT cell survival, a clinically effective small-molecule inhibitor remains elusive likely because EWS-FLI1 is a transcription factor and therefore widely felt to be "undruggable...
June 22, 2011: Journal of the National Cancer Institute
Paul M Neilsen, Kathleen I Pishas, David F Callen, David M Thomas
The p53 tumour suppressor plays a pivotal role in the prevention of oncogenic transformation. Cancers frequently evade the potent antitumour surveillance mechanisms of p53 through mutation of the TP53 gene, with approximately 50% of all human malignancies expressing dysfunctional, mutated p53 proteins. Interestingly, genetic lesions in the TP53 gene are only observed in 10% of Ewing Sarcomas, with the majority of these sarcomas expressing a functional wild-type p53. In addition, the p53 downstream signaling pathways and DNA-damage cell cycle checkpoints remain functionally intact in these sarcomas...
2011: Sarcoma
Yan Li, Kazuhiro Tanaka, Xueli Fan, Fumihiko Nakatani, Xu Li, Tomoyuki Nakamura, Minoru Takasaki, Shunsaku Yamamoto, Yukihide Iwamoto
The chromosomal translocation t(11;22)(q24;q12) generates the EWS-Fli1 fusion gene, which contributes to the development of Ewing Family Tumors (EFTs). Although p53 mutations are found only in 5-20% of EFTs, the p53 pathway is thought to be abrogated in EFTs. The role of EWS-Fli1 in the p53 pathway in the tumor is still poorly understood. In this study, using immunoprecipitation and co-localization, we show that EWS-Fli1 interacts with p53 within the nucleus in vivo. The introduction of EWS-Fli1 resulted in significant reduction of promoter activities and mRNA levels of p21 and mdm2, meanwhile it canceled p53-dependent growth suppression...
August 1, 2010: Cancer Letters
Maximilian Kauer, Jozef Ban, Reinhard Kofler, Bob Walker, Sean Davis, Paul Meltzer, Heinrich Kovar
BACKGROUND: EWS-FLI1 is a chimeric ETS transcription factor that is, due to a chromosomal rearrangement, specifically expressed in Ewing's sarcoma family tumors (ESFT) and is thought to initiate the development of the disease. Previous genomic profiling experiments have identified EWS-FLI1-regulated genes and genes that discriminate ESFT from other sarcomas, but so far a comprehensive analysis of EWS-FLI1-dependent molecular functions characterizing this aggressive cancer is lacking. METHODOLOGY/PRINCIPAL FINDINGS: In this study, a molecular function map of ESFT was constructed based on an integrative analysis of gene expression profiling experiments following EWS-FLI1 knockdown in a panel of five ESFT cell lines, and on gene expression data from the same platform of 59 primary ESFT...
2009: PloS One
Iva V Klevernic, Simon Morton, Roger J Davis, Philip Cohen
In Ewing's sarcomas, chromosomal translocations cause the N-terminal domain of the EWS (Ewing's sarcoma protein) to fuse with the DNA-binding domains of the Ets (E26 transformation-specific) family of transcription factors. Here we show that EWS and EWS-Fli1 (Friend leukaemia virus integration 1), the fusion most frequently found in Ewing's sarcomas, become phosphorylated at Thr(79) in response to either mitogens or DNA-damaging agents. The much weaker mitogen-induced phosphorylation of EWS is catalysed by the MAPKs (mitogen-activated protein kinases) ERK1 (extracellular signal-regulated kinase 1) and ERK2, whereas the much stronger phosphorylation of EWS induced by the DNA alkylating agent MMS (methyl methanesulphonate) can be catalysed by JNK (c-Jun N-terminal kinase) and at least one other protein kinase distinct from ERK1/ERK2...
March 15, 2009: Biochemical Journal
Heinrich Kovar, Sarka Pospisilova, Gunhild Jug, Dieter Printz, Helmut Gadner
The EWS-FLI1 transcription factor is consistently expressed in 85% of Ewing tumors (EFT). In heterologous cells, EWS-FLI1 induces p53-dependent cell cycle arrest or apoptosis. It has been speculated that the p53 tumor suppressor pathway may be generally compromised in EFT despite only rare p53 mutations. In order to test for functional integrity of this pathway, we have investigated a series of EFT cell lines that differ from each other with respect to their endogenous p53 and INK4A gene status for their response to ectopic p53 expression and to stimulation of endogenous p53 activity by X-ray treatment...
May 22, 2003: Oncogene
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