Oncogenic Partnerships: EWS-FLI1 Protein Interactions Initiate Key Pathways of Ewing's Sarcoma

Targeted therapy for cancer, which is specifically directed toward the cancer without any potential for effects outside of controlling the tumor, is a gold standard for treatment. Ewing's sarcoma contains the potential target EWS-FLI1, as a result of a pathognomonic chromosomal translocation. The EWS-FLI1 fusion protein includes the EWS domain, a potent transcriptional activator alongside the highly conserved FLI1 ets DNA-binding domain. Because of the combination of these domains, the EWS-FLI1 fusion protein acts as an aberrant transcription factor whose expression results in cellular transformation. EWS-FLI1 functions by binding to normal cellular protein partners in transcription and splicing, similar to how a virus would corrupt normal cellular machinery for virion production. Therefore, understanding the protein-protein interactions of EWS-FLI1 and the pathways that are regulated by these partnerships will inform both oncogenesis and therapeutics. This review describes the known protein partners and transcriptional targets of EWS-FLI1, while proposing strategies for exploiting these partnerships with targeted therapy. Clin Cancer Res; 16(16); 4077–83. ©2010 AACR.

[1]  Peter J Houghton,et al.  Initial testing of the aurora kinase a inhibitor MLN8237 by the Pediatric Preclinical Testing Program (PPTP) , 2010, Pediatric blood & cancer.

[2]  S. Keir,et al.  Initial testing of a monoclonal antibody (IMC‐A12) against IGF‐1R by the pediatric preclinical testing program , 2010, Pediatric blood & cancer.

[3]  S. Schuetze,et al.  Safety, pharmacokinetics, and preliminary activity of the anti-IGF-1R antibody figitumumab (CP-751,871) in patients with sarcoma and Ewing's sarcoma: a phase 1 expansion cohort study. , 2010, The Lancet. Oncology.

[4]  S. Lessnick,et al.  EWS/FLI and its downstream target NR0B1 interact directly to modulate transcription and oncogenesis in Ewing's sarcoma. , 2009, Cancer research.

[5]  S. Lessnick,et al.  GSTM4 is a microsatellite-containing EWS/FLI target involved in Ewing's sarcoma oncogenesis and therapeutic resistance , 2009, Oncogene.

[6]  B. Roschitzki,et al.  Analysis of Ewing sarcoma (EWS)-binding proteins: interaction with hnRNP M, U, and RNA-helicases p68/72 within protein-RNA complexes. , 2009, Journal of proteome research.

[7]  Nicolò Riggi,et al.  Ewing’s sarcoma origin: from duel to duality , 2009, Expert review of anticancer therapy.

[8]  P. Meltzer,et al.  A Molecular Function Map of Ewing's Sarcoma , 2009, PloS one.

[9]  A. Üren,et al.  GLI1 Is a Direct Transcriptional Target of EWS-FLI1 Oncoprotein* , 2009, Journal of Biological Chemistry.

[10]  P. Cohen,et al.  Phosphorylation of Ewing's sarcoma protein (EWS) and EWS-Fli1 in response to DNA damage. , 2009, The Biochemical journal.

[11]  H Kovar,et al.  O-GlcNAcylation is involved in the transcriptional activity of EWS-FLI1 in Ewing's sarcoma , 2009, Oncogene.

[12]  H. Kovar,et al.  EZH2 is a mediator of EWS/FLI1 driven tumor growth and metastasis blocking endothelial and neuro-ectodermal differentiation , 2009, Proceedings of the National Academy of Sciences.

[13]  R. Andino,et al.  An Amphipathic α-Helix Controls Multiple Roles of Brome Mosaic Virus Protein 1a in RNA Replication Complex Assembly and Function , 2009, PLoS pathogens.

[14]  A. Üren,et al.  A small molecule blocking oncogenic protein EWS-FLI1 interaction with RNA helicase A inhibits growth of Ewing’s sarcoma , 2009 .

[15]  Y. Okano,et al.  EWS-Fli1 Up-Regulates Expression of the Aurora A and Aurora B Kinases , 2008, Molecular Cancer Research.

[16]  Mike Tyers,et al.  Dynamic equilibrium engagement of a polyvalent ligand with a single-site receptor , 2008, Proceedings of the National Academy of Sciences.

[17]  E. Lalli,et al.  DAX1, a direct target of EWS/FLI1 oncoprotein, is a principal regulator of cell-cycle progression in Ewing's tumor cells , 2008, Oncogene.

[18]  J. Ludwig Ewing sarcoma: historical perspectives, current state-of-the-art, and opportunities for targeted therapy in the future , 2008, Current opinion in oncology.

[19]  T. Triche,et al.  The EWS/FLI1 oncogenic transcription factor deregulates GLI1 , 2008, Oncogene.

[20]  Christopher J. Oldfield,et al.  Intrinsically disordered proteins in human diseases: introducing the D2 concept. , 2008, Annual review of biophysics.

[21]  O. Delattre,et al.  Alteration of cyclin D1 transcript elongation by a mutated transcription factor up-regulates the oncogenic D1b splice isoform in cancer , 2008, Proceedings of the National Academy of Sciences.

[22]  M. Suvà,et al.  EWS-FLI-1 expression triggers a Ewing's sarcoma initiation program in primary human mesenchymal stem cells. , 2008, Cancer research.

[23]  若原 和彦 EWS-Fli1 up-regulates expression of the Aurora A and Aurora B kinases , 2008 .

[24]  Chuan-miao Xie,et al.  [CT and MRI features of peripheral primitive neuroectodermal tumor]. , 2007, Ai zheng = Aizheng = Chinese journal of cancer.

[25]  C. Nanni,et al.  Preclinical In vivo Study of New Insulin-Like Growth Factor-I Receptor–Specific Inhibitor in Ewing's Sarcoma , 2007, Clinical Cancer Research.

[26]  Vladimir N Uversky,et al.  Multiple aromatic side chains within a disordered structure are critical for transcription and transforming activity of EWS family oncoproteins , 2007, Proceedings of the National Academy of Sciences.

[27]  S. Gellman,et al.  Targeting protein-protein interactions: lessons from p53/MDM2. , 2007, Biopolymers.

[28]  S. Lessnick,et al.  NR0B1 Is Required for the Oncogenic Phenotype Mediated by EWS/FLI in Ewing's Sarcoma , 2006, Molecular Cancer Research.

[29]  J. Ban,et al.  Caveolin-1 (CAV1) is a target of EWS/FLI-1 and a key determinant of the oncogenic phenotype and tumorigenicity of Ewing's sarcoma cells. , 2006, Cancer research.

[30]  T. Nielsen Microarray Analysis of Sarcomas , 2006, Advances in anatomic pathology.

[31]  J. Parvin,et al.  Oncoprotein EWS-FLI1 activity is enhanced by RNA helicase A. , 2006, Cancer research.

[32]  Theresa A. Storm,et al.  Fatality in mice due to oversaturation of cellular microRNA/short hairpin RNA pathways , 2006, Nature.

[33]  Cheryl Bolinger,et al.  RNA helicase A is necessary for translation of selected messenger RNAs , 2006, Nature Structural &Molecular Biology.

[34]  C. Denny,et al.  Cooperative DNA Binding with AP-1 Proteins Is Required for Transformation by EWS-Ets Fusion Proteins , 2006, Molecular and Cellular Biology.

[35]  O. Delattre,et al.  The orphan nuclear receptor DAX1 is up‐regulated by the EWS/FLI1 oncoprotein and is highly expressed in Ewing tumors , 2006, International journal of cancer.

[36]  S. Lessnick,et al.  NR 0 B 1 Is Required for the Oncogenic Phenotype Mediated by EWS / FLI in Ewing ’ s Sarcoma , 2006 .

[37]  Mark E. Davis,et al.  Sequence-specific knockdown of EWS-FLI1 by targeted, nonviral delivery of small interfering RNA inhibits tumor growth in a murine model of metastatic Ewing's sarcoma. , 2005, Cancer research.

[38]  Y. Banno,et al.  Inhibition of Platelet-derived Growth Factor-induced Cell Growth Signaling by a Short Interfering RNA for EWS-Fli1 via Down-regulation of Phospholipase D2 in Ewing Sarcoma Cells* , 2005, Journal of Biological Chemistry.

[39]  J. Toretsky,et al.  Ewing's sarcoma oncoprotein EWS-FLI1: the perfect target without a therapeutic agent. , 2005, Future oncology.

[40]  H. Kovar Context matters: the hen or egg problem in Ewing's sarcoma. , 2005, Seminars in cancer biology.

[41]  J. Ban,et al.  EWS-FLI1 target genes recovered from Ewing's sarcoma chromatin , 2005, Oncogene.

[42]  Richard S Larson,et al.  Design and structure of peptide and peptidomimetic antagonists of protein-protein interaction. , 2005, Current protein & peptide science.

[43]  野澤 聡 Inhibition of platelet-derived growth factor-induced cell growth signaling by a short interfering RNA for EWS-Fli1 via down-regulation of phospholipase D2 in Ewing sarcoma cells , 2005 .

[44]  J. Toretsky,et al.  Recombinant EWS-FLI1 oncoprotein activates transcription. , 2004, Biochemistry.

[45]  Leo M. Lee,et al.  Role of protein–protein interactions in the antiapoptotic function of EWS-Fli-1 , 2004, Oncogene.

[46]  K. Audouze,et al.  Emerging classes of protein-protein interaction inhibitors and new tools for their development. , 2004, Current opinion in chemical biology.

[47]  Michelle R. Arkin,et al.  Small-molecule inhibitors of protein–protein interactions: progressing towards the dream , 2004, Nature Reviews Drug Discovery.

[48]  J. S. Sodhi,et al.  Prediction and functional analysis of native disorder in proteins from the three kingdoms of life. , 2004, Journal of molecular biology.

[49]  中谷 文彦 Identification of p21WAF1/CIP1 as a direct target of EWS-Fli1 oncogenic fusion protein , 2004 .

[50]  N. Bhat,et al.  Inhibition of EWS-FLI-1 fusion protein with antisense oligodeoxynucleotides , 2004, Journal of Neuro-Oncology.

[51]  P. Couvreur,et al.  Therapeutic Potentialities of EWS‐Fli‐1 mRNA‐Targeted Vectorized Antisense Oligonucleotides , 2003, Annals of the New York Academy of Sciences.

[52]  T. Taira,et al.  EWS/ETS fusions activate telomerase in Ewing's tumors. , 2003, Cancer research.

[53]  C. Denny,et al.  Functional analysis of the EWS/ETS target gene uridine phosphorylase. , 2003, Cancer research.

[54]  Y. Iwamoto,et al.  Identification of p21 WAF1/CIP1 as a Direct Target of EWS-Fli1 Oncogenic Fusion Protein* , 2003, The Journal of Biological Chemistry.

[55]  H. Kovar,et al.  Interaction of the EWS NH2 terminus with BARD1 links the Ewing's sarcoma gene to a common tumor suppressor pathway. , 2002, Cancer research.

[56]  S. Welford,et al.  The COOH-terminal domain of FLI-1 is necessary for full tumorigenesis and transcriptional modulation by EWS/FLI-1. , 2001, Cancer research.

[57]  S. Baker,et al.  EWS/FLI Alters 5′-Splice Site Selection* , 2001, The Journal of Biological Chemistry.

[58]  M. Ringnér,et al.  Classification and diagnostic prediction of cancers using gene expression profiling and artificial neural networks , 2001, Nature Medicine.

[59]  H. Chansky,et al.  Oncogenic TLS/ERG and EWS/Fli-1 fusion proteins inhibit RNA splicing mediated by YB-1 protein. , 2001, Cancer research.

[60]  Runzhao Li,et al.  Regulation of Ets function by protein–protein interactions , 2000, Oncogene.

[61]  H. Chansky,et al.  EWS·Fli-1 Fusion Protein Interacts with Hyperphosphorylated RNA Polymerase II and Interferes with Serine-Arginine Protein-mediated RNA Splicing* , 2000, The Journal of Biological Chemistry.

[62]  W. Sommergruber,et al.  Variability in Gene Expression Patterns of Ewing Tumor Cell Lines Differing in EWS-FLI1 Fusion Type , 2000, Laboratory Investigation.

[63]  S. Baker,et al.  The Splicing Factor U1C Represses EWS/FLI-mediated Transactivation* , 2000, The Journal of Biological Chemistry.

[64]  C. Brown,et al.  Intrinsic protein disorder in complete genomes. , 2000, Genome informatics. Workshop on Genome Informatics.

[65]  Erica A Golemis,et al.  Oncogenic EWS-Fli1 interacts with hsRPB7, a subunit of human RNA polymerase II , 1998, Oncogene.

[66]  Olivier Delattre,et al.  EWS, but Not EWS-FLI-1, Is Associated with Both TFIID and RNA Polymerase II: Interactions between Two Members of the TET Family, EWS and hTAFII68, and Subunits of TFIID and RNA Polymerase II Complexes , 1998, Molecular and Cellular Biology.

[67]  D. Leroith,et al.  The Insulin-like Growth Factor-I Receptor Is Required for EWS/FLI-1 Transformation of Fibroblasts* , 1997, The Journal of Biological Chemistry.

[68]  Jeffrey D. Parvin,et al.  RNA Helicase A Mediates Association of CBP with RNA Polymerase II , 1997, Cell.

[69]  I. Kola,et al.  FLI1 and EWS-FLI1 function as ternary complex factors and ELK1 and SAP1a function as ternary and quaternary complex factors on the Egr1 promoter serum response elements , 1997, Oncogene.

[70]  K. Tanaka,et al.  EWS-Fli1 antisense oligodeoxynucleotide inhibits proliferation of human Ewing's sarcoma and primitive neuroectodermal tumor cells. , 1997, The Journal of clinical investigation.

[71]  M. Schemper,et al.  EWS/FLI-1 antagonists induce growth inhibition of Ewing tumor cells in vitro. , 1996, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[72]  M. Ouchida,et al.  Loss of tumorigenicity of Ewing's sarcoma cells expressing antisense RNA to EWS-fusion transcripts. , 1995, Oncogene.

[73]  T. Triche,et al.  The Ewing family of tumors--a subgroup of small-round-cell tumors defined by specific chimeric transcripts. , 1994, The New England journal of medicine.

[74]  M. Roussel,et al.  DNA-binding and transcriptional activation properties of the EWS-FLI-1 fusion protein resulting from the t(11;22) translocation in Ewing sarcoma , 1994, Molecular and cellular biology.

[75]  C. Denny,et al.  The Ewing's sarcoma EWS/FLI-1 fusion gene encodes a more potent transcriptional activator and is a more powerful transforming gene than FLI-1 , 1993, Molecular and cellular biology.

[76]  G. Thomas,et al.  Gene fusion with an ETS DNA-binding domain caused by chromosome translocation in human tumours , 1992, Nature.