Targeting the epigenetic readers in Ewing Sarcoma inhibits the oncogenic transcription factor EWS/Fli1

Oncotarget

Volumn 7, Issue 17, 2016, Pages 24125-24140

  Jacques, Camille ^a,b   Lamoureux, François ^a,b   Baud'huin, Marc ^a,b,c   Calleja, Lidia Rodriguez ^a,b   Quillard, Thibaut ^a,b   Amiaud, Jérôme ^a,b   Tirode, Franck ^d   Rédini, Françoise ^a,b   Bradner, James E ^e   Heymann, Dominique ^a,b,c   Ory, Benjamin ^a,b  

^a INSERM   (France)

^b UNIVERSITÉ DE NANTES   (France)

^c NANTES UNIVERSITY HOSPITAL   (France)

^d INSTITUT CURIE   (France)

^e HARVARD MEDICAL SCHOOL   (United States)

Author keywords

Bromodomain; Epigenetic; Ewing sarcoma; EWS Fli1; JQ1

Indexed keywords

4 (4 CHLOROPHENYL) 2,3,9 TRIMETHYL 6H THIENO[3,2 F][1,2,4]TRIAZOLO[4,3 A][1,4]DIAZEPINE 6 ACETIC ACID TERT BUTYL ESTER; PEPTIDES AND PROTEINS; PROTEIN BRD4; PROTEIN FLI1; RNA BINDING PROTEIN EWS; UNCLASSIFIED DRUG; (+)-JQ1 COMPOUND; AZEPINE DERIVATIVE; BROMODOMAIN AND EXTRA-TERMINAL DOMAIN PROTEIN, HUMAN; EWS-FLI FUSION PROTEIN; ONCOPROTEIN; PROTEIN; TRANSCRIPTION FACTOR FLI 1; TRIAZOLE DERIVATIVE; TUMOR MARKER;

ADOLESCENT; ADULT; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; APOPTOSIS; ARTICLE; CANCER CHEMOTHERAPY; CANCER SPECIFIC SURVIVAL; CARCINOGENESIS; CELL MIGRATION; CELL VIABILITY; CHROMATIN IMMUNOPRECIPITATION; CLONOGENESIS; CONCENTRATION RESPONSE; CONTROLLED STUDY; EPIGENETICS; EWING SARCOMA; FEMALE; G1 PHASE CELL CYCLE CHECKPOINT; HUMAN; HUMAN CELL; IN VITRO STUDY; IN VIVO STUDY; MALE; MOUSE; NONHUMAN; OVERALL SURVIVAL; TRANSCRIPTION REGULATION; YOUNG ADULT; ANIMAL; ANTAGONISTS AND INHIBITORS; BONE TUMOR; CELL CYCLE; CELL MOTION; CELL PROLIFERATION; DRUG EFFECTS; DRUG SCREENING; GENE EXPRESSION REGULATION; GENETIC EPIGENESIS; GENETICS; NUDE MOUSE; PATHOLOGY; TUMOR CELL CULTURE;

ADOLESCENT; ADULT; ANIMALS; APOPTOSIS; AZEPINES; BIOMARKERS, TUMOR; BONE NEOPLASMS; CELL CYCLE; CELL MOVEMENT; CELL PROLIFERATION; EPIGENESIS, GENETIC; FEMALE; GENE EXPRESSION REGULATION, NEOPLASTIC; HUMANS; MALE; MICE; MICE, NUDE; ONCOGENE PROTEINS, FUSION; PROTEINS; PROTO-ONCOGENE PROTEIN C-FLI-1; RNA-BINDING PROTEIN EWS; SARCOMA, EWING; TRIAZOLES; TUMOR CELLS, CULTURED; XENOGRAFT MODEL ANTITUMOR ASSAYS; YOUNG ADULT;

EID: 84966586078     PISSN: None     EISSN: 19492553     Source Type: Journal    
DOI: 10.18632/oncotarget.8214     Document Type: Article

References (58)

1. Bernstein M, Kovar H, Paulussen M, Randall RL, Schuck A, Teot LA, Juergens H. Ewing's sarcoma family of tumors: current management. Oncologist. 2006; 11:503-519.
2. Ewing J. Classics in oncology. Diffuse endothelioma of bone. James Ewing. Proceedings of the New York Pathological Society, 1921. CA Cancer J Clin. 1972; 22: 95-98.
3. Schuck A, Ahrens S, Paulussen M, Kuhlen M, Konemann S, Rube C, Winkelmann W, Kotz R, Dunst J, Willich N, Jurgens H. Local therapy in localized Ewing tumors: results of 1058 patients treated in the CESS 81, CESS 86, and EICESS 92 trials. Int J Radiat Oncol Biol Phys. 2003; 55:168-177.
4. Grier HE, Krailo MD, Tarbell NJ, Link MP, Fryer CJ, Pritchard DJ, Gebhardt MC, Dickman PS, Perlman EJ, Meyers PA, Donaldson SS, Moore S, Rausen AR, et al. Addition of ifosfamide and etoposide to standard chemotherapy for Ewing's sarcoma and primitive neuroectodermal tumor of bone. N Engl J Med. 2003; 348:694-701.
5. Paulussen M, Craft AW, Lewis I, Hackshaw A, Douglas C, Dunst J, Schuck A, Winkelmann W, Kohler G, Poremba C, Zoubek A, Ladenstein R, van den Berg H, et al. Results of the EICESS-92 Study: two randomized trials of Ewing's sarcoma treatment-cyclophosphamide compared with ifosfamide in standard-risk patients and assessment of benefit of etoposide added to standard treatment in highrisk patients. J Clin Oncol. 2008; 26:4385-4393.
6. Bone sarcomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014; 25:iii113-123.
7. Delattre O, Zucman J, Plougastel B, Desmaze C, Melot T, Peter M, Kovar H, Joubert I, de Jong P, Rouleau G, et al. Gene fusion with an ETS DNA-binding domain caused by chromosome translocation in human tumours. Nature. 1992; 359:162-165.
8. May WA, Lessnick SL, Braun BS, Klemsz M, Lewis BC, Lunsford LB, Hromas R, Denny CT. 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. Mol Cell Biol. 1993; 13:7393-7398.
9. Bailly RA, Bosselut R, Zucman J, Cormier F, Delattre O, Roussel M, Thomas G, Ghysdael J. DNA-binding and transcriptional activation properties of the EWS-FLI-1 fusion protein resulting from the t (11; 22) translocation in Ewing sarcoma. Mol Cell Biol. 1994; 14:3230-3241.
10. Dauphinot L, De Oliveira C, Melot T, Sevenet N, Thomas V, Weissman BE, Delattre O. Analysis of the expression of cell cycle regulators in Ewing cell lines: EWS-FLI-1 modulates p57KIP2and c-Myc expression. Oncogene. 2001; 20: 3258-3265.
11. Fukuma M, Okita H, Hata J, Umezawa A. Upregulation of Id2, an oncogenic helix-loop-helix protein, is mediated by the chimeric EWS/ets protein in Ewing sarcoma. Oncogene. 2003; 22:1-9.
12. Matsumoto Y, Tanaka K, Nakatani F, Matsunobu T, Matsuda S, Iwamoto Y. Downregulation and forced expression of EWS-Fli1 fusion gene results in changes in the expression of G (1) regulatory genes. Br J Cancer. 2001; 84:768-775.
13. Beauchamp E, Bulut G, Abaan O, Chen K, Merchant A, Matsui W, Endo Y, Rubin JS, Toretsky J, Uren A. GLI1 is a direct transcriptional target of EWS-FLI1 oncoprotein. J Biol Chem. 2009; 284:9074-9082.
14. Braun BS, Frieden R, Lessnick SL, May WA, Denny CT. Identification of target genes for the Ewing's sarcoma EWS/ FLI fusion protein by representational difference analysis. Mol Cell Biol. 1995; 15:4623-4630.
15. Fuchs B, Inwards CY, Janknecht R. Vascular endothelial growth factor expression is up-regulated by EWS-ETS oncoproteins and Sp1 and may represent an independent predictor of survival in Ewing's sarcoma. Clin Cancer Res. 2004; 10:1344-1353.
16. Nagano A, Ohno T, Shimizu K, Hara A, Yamamoto T, Kawai G, Saitou M, Takigami I, Matsuhashi A, Yamada K, Takei Y. EWS/Fli-1 chimeric fusion gene upregulates vascular endothelial growth factor-A. Int J Cancer. 2010; 126:2790-2798.
17. Mendiola M, Carrillo J, Garcia E, Lalli E, Hernandez T, de Alava E, Tirode F, Delattre O, Garcia-Miguel P, Lopez-Barea F, Pestana A, Alonso J. The orphan nuclear receptor DAX1 is up-regulated by the EWS/FLI1 oncoprotein and is highly expressed in Ewing tumors. Int J Cancer. 2006; 118:1381-1389.
18. Garcia-Aragoncillo E, Carrillo J, Lalli E, Agra N, Gomez-Lopez G, Pestana A, Alonso J. DAX1, a direct target of EWS/FLI1 oncoprotein, is a principal regulator of cellcycle progression in Ewing's tumor cells. Oncogene. 2008; 27:6034-6043.
19. Christensen L, Joo J, Lee S, Wai D, Triche TJ, May WA. FOXM1 is an oncogenic mediator in Ewing Sarcoma. PLoS ONE. 2013; 8:e54556.
20. Richter GH, Plehm S, Fasan A, Rossler S, Unland R, Bennani-Baiti IM, Hotfilder M, Lowel D, von Luettichau I, Mossbrugger I, Quintanilla-Martinez L, Kovar H, Staege MS, et al. EZH2 is a mediator of EWS/FLI1 driven tumor growth and metastasis blocking endothelial and neuroectodermal differentiation. Proc Natl Acad Sci U S A. 2009; 106:5324-5329.
21. Hahm KB, Cho K, Lee C, Im YH, Chang J, Choi SG, Sorensen PH, Thiele CJ, Kim SJ. Repression of the gene encoding the TGF-beta type II receptor is a major target of the EWS-FLI1 oncoprotein. Nat Genet. 1999; 23:222-227.
22. Nakatani F, Tanaka K, Sakimura R, Matsumoto Y, Matsunobu T, Li X, Hanada M, Okada T, Iwamoto Y. Identification of p21WAF1/CIP1 as a direct target of EWS-Fli1 oncogenic fusion protein. J Biol Chem. 2003; 278:15105-15115.
23. Im YH, Kim HT, Lee C, Poulin D, Welford S, Sorensen PH, Denny CT, Kim SJ. EWS-FLI1, EWS-ERG, and EWSETV1 oncoproteins of Ewing tumor family all suppress transcription of transforming growth factor beta type II receptor gene. Cancer Res. 2000; 60:1536-1540.
24. Prieur A, Tirode F, Cohen P, Delattre O. EWS/FLI-1 silencing and gene profiling of Ewing cells reveal downstream oncogenic pathways and a crucial role for repression of insulin-like growth factor binding protein 3. Mol Cell Biol. 2004; 24:7275-7283.
25. Kovar H. Downstream EWS/FLI1 -upstream Ewing's sarcoma. Genome Med. 2010; 2:8.
26. Tanaka K, Iwakuma T, Harimaya K, Sato H, Iwamoto Y. EWS-Fli1 antisense oligodeoxynucleotide inhibits proliferation of human Ewing's sarcoma and primitive neuroectodermal tumor cells. J Clin Invest. 1997; 99: 239-247.
27. Hewings DS, Rooney TP, Jennings LE, Hay DA, Schofield CJ, Brennan PE, Knapp S, Conway SJ. Progress in the development and application of small molecule inhibitors of bromodomain-acetyl-lysine interactions. J Med Chem. 2012; 55:9393-9413.
28. Prinjha RK, Witherington J, Lee K. Place your BETs: the therapeutic potential of bromodomains. Trends Pharmacol Sci. 2012; 33:146-153.
29. Yang Z, He N, Zhou Q. Brd4 recruits P-TEFb to chromosomes at late mitosis to promote G1 gene expression and cell cycle progression. Mol Cell Biol. 2008; 28: 967-976.
30. Bandopadhayay P, Bergthold G, Nguyen B, Schubert S, Gholamin S, Tang Y, Bolin S, Schumacher SE, Zeid R, Masoud S, Yu F, Vue N, Gibson WJ, et al. BET bromodomain inhibition of MYC-amplified medulloblastoma. Clin Cancer Res. 2014; 20:912-925.
31. Lamoureux F, Baud'huin M, Rodriguez Calleja L, Jacques C, Berreur M, Redini F, Lecanda F, Bradner JE, Heymann D, Ory B. Selective inhibition of BET bromodomain epigenetic signalling interferes with the boneassociated tumour vicious cycle. Nature communications. 2014; 5:3511.
32. Delmore JE, Issa GC, Lemieux ME, Rahl PB, Shi J, Jacobs HM, Kastritis E, Gilpatrick T, Paranal RM, Qi J, Chesi M, Schinzel AC, McKeown MR, et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011; 146:904-917.
33. Dawson MA, Prinjha RK, Dittmann A, Giotopoulos G, Bantscheff M, Chan WI, Robson SC, Chung CW, Hopf C, Savitski MM, Huthmacher C, Gudgin E, Lugo D, et al. Inhibition of BET recruitment to chromatin as an effective treatment for MLL -fusion leukaemia. Nature. 2011; 478:529-533.
34. Zuber J, Shi J, Wang E, Rappaport AR, Herrmann H, Sison EA, Magoon D, Qi J, Blatt K, Wunderlich M, Taylor MJ, Johns C, Chicas A, et al. RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia. Nature. 2011; 478: 524-528.
35. Komori T. Runx2, a multifunctional transcription factor in skeletal development. J Cell Biochem. 2002; 87:1-8.
36. Pande S, Browne G, Padmanabhan S, Zaidi SK, Lian JB, van Wijnen AJ, Stein JL, Stein GS. Oncogenic cooperation between PI3K/Akt signaling and transcription factor Runx2 promotes the invasive properties of metastatic breast cancer cells. J Cell Physiol. 2013; 228:1784-1792.
37. Beesley AH, Stirnweiss A, Ferrari E, Endersby R, Howlett M, Failes TW, Arndt GM, Charles AK, Cole CH, Kees UR. Comparative drug screening in NUT midline carcinoma. Br J Cancer. 2014; 110:1189-1198.
38. Fiskus W, Sharma S, Qi J, Shah B, Devaraj SG, Leveque C, Portier BP, Iyer S, Bradner JE, Bhalla KN. BET protein antagonist JQ1 is synergistically lethal with FLT3 tyrosine kinase inhibitor (TKI) and overcomes resistance to FLT3-TKI in AML cells expressing FLT-ITD. Mol Cancer Ther. 2014; 13:2315-2327.
39. Shimamura T, Chen Z, Soucheray M, Carretero J, Kikuchi E, Tchaicha JH, Gao Y, Cheng KA, Cohoon TJ, Qi J, Akbay E, Kimmelman AC, Kung AL, et al. Efficacy of BET bromodomain inhibition in Kras-mutant non-small cell lung cancer. Clin Cancer Res. 2013; 19:6183-6192.
40. Lochrin SE, Price DK, Figg WD. BET bromodomain inhibitors-a novel epigenetic approach in castrationresistant prostate cancer. Cancer Biol Ther. 2014; 15:1583-1585.
41. L oven J, Hoke HA, Lin CY, Lau A, Orlando DA, Vakoc CR, Bradner JE, Lee TI, Young RA. Selective inhibition of tumor oncogenes by disruption of super-enhancers. Cell. 2013; 153:320-334.
42. Hnisz D, Schuijers J, Lin CY, Weintraub AS, Abraham BJ, Lee TI, Bradner JE, Young RA. Convergence of developmental and oncogenic signaling pathways at transcriptional super-enhancers. Mol Cell. 2015; 58:362-370.
43. Tomazou EM, Sheffield NC, Schmidl C, Schuster M, Schonegger A, Datlinger P, Kubicek S, Bock C, Kovar H. Epigenome Mapping Reveals Distinct Modes of Gene Regulation and Widespread Enhancer Reprogramming by the Oncogenic Fusion Protein EWS-FLI1. Cell Rep. 2015; 10:1082-1095.
44. Filippakopoulos P, Qi J, Picaud S, Shen Y, Smith WB, Fedorov O, Morse EM, Keates T, Hickman TT, Felletar I, Philpott M, Munro S, McKeown MR, et al. Selective inhibition of BET bromodomains. Nature. 2010; 468:1067-1073.
45. Hensel T, Giorgi C, Schmidt O, Calzada-Wack J, Neff F, Buch T, Niggli FK, Schafer BW, Burdach S, Richter GH. Targeting the EWS-ETS transcriptional program by BET bromodomain inhibition in Ewing sarcoma. Oncotarget. 2016; 7:1451-63. doi: 10.18632/oncotarget.6385.
46. Hu-Lieskovan S, Heidel JD, Bartlett DW, Davis ME, Triche TJ. 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. Cancer Res. 2005; 65:8984-8992.
47. Whyte WA, Orlando DA, Hnisz D, Abraham BJ, Lin CY, Kagey MH, Rahl PB, Lee TI, Young RA. Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell. 2013; 153:307-319.
48. Zwerner JP, Joo J, Warner KL, Christensen L, Hu-Lieskovan S, Triche TJ, May WA. The EWS/FLI1 oncogenic transcription factor deregulates GLI1. Oncogene. 2008; 27:3282-3291.
49. Chandhanayingyong C, Kim Y, Staples JR, Hahn C, Lee FY. MAPK/ERK Signaling in Osteosarcomas, Ewing Sarcomas and Chondrosarcomas: Therapeutic Implications and Future Directions. Sarcoma. 2012; 2012:404810.
50. Silvany RE, Eliazer S, Wolff NC, Ilaria RL, Jr. Interference with the constitutive activation of ERK1 and ERK2 impairs EWS/FLI-1-dependent transformation. Oncogene. 2000; 19:4523-4530.
51. Grohar PJ, Woldemichael GM, Griffin LB, Mendoza A, Chen QR, Yeung C, Currier DG, Davis S, Khanna C, Khan J, McMahon JB, Helman LJ. Identification of an inhibitor of the EWS-FLI1 oncogenic transcription factor by high-throughput screening. J Natl Cancer Inst. 2011; 103:962-978.
52. Erkizan HV, Kong Y, Merchant M, Schlottmann S, Barber-Rotenberg JS, Yuan L, Abaan OD, Chou TH, Dakshanamurthy S, Brown ML, Uren A, Toretsky JA. A small molecule blocking oncogenic protein EWS-FLI1 interaction with RNA helicase A inhibits growth of Ewing's sarcoma. Nat Med. 2009; 15:750-756.
53. Grohar PJ, Griffin LB, Yeung C, Chen QR, Pommier Y, Khanna C, Khan J, Helman LJ. Ecteinascidin 743 interferes with the activity of EWS-FLI1 in Ewing sarcoma cells. Neoplasia. 2011; 13:145-153.
54. Pott S, Lieb JD. What are super-enhancers? Nat Genet. 2015; 47:8-12.
55. Beauchamp EM, Ringer L, Bulut G, Sajwan KP, Hall MD, Lee YC, Peaceman D, Ozdemirli M, Rodriguez O, Macdonald TJ, Albanese C, Toretsky JA, Uren A. Arsenic trioxide inhibits human cancer cell growth and tumor development in mice by blocking Hedgehog/GLI pathway. J Clin Invest. 2011; 121:148-160.
56. Sengupta A, Rahman M, Mateo-Lozano S, Tirado OM, Notario V. The dual inhibitory effect of thiostrepton on FoxM1 and EWS/FLI1 provides a novel therapeutic option for Ewing's sarcoma. Int J Oncol. 2013; 43:803-812.
57. Kinsey M, Smith R, Lessnick SL. NR0B1 is required for the oncogenic phenotype mediated by EWS/FLI in Ewing's sarcoma. Mol Cancer Res. 2006; 4:851-859.
58. Yudoh K, Kanamori M, Ohmori K, Yasuda T, Aoki M, Kimura T. Concentration of vascular endothelial growth factor in the tumour tissue as a prognostic factor of soft tissue sarcomas. Br J Cancer. 2001; 84:1610-1615.