title: Targeting the EWS-ETS transcriptional program by BET bromodomain inhibition in Ewing sarcoma.
abstract: Ewing sarcomas (ES) are highly malignant bone or soft tissue tumors. Genetically, ES are defined by balanced chromosomal EWS/ETS translocations, which give rise to chimeric proteins (EWS-ETS) that generate an oncogenic transcriptional program associated with altered epigenetic marks throughout the genome. By use of an inhibitor (JQ1) blocking BET bromodomain binding proteins (BRDs) we strikingly observed a strong down-regulation of the predominant EWS-ETS protein EWS-FLI1 in a dose dependent manner. This was further enhanced by co-treatment with an inhibitor of the PI3K pathway. Microarray analysis further revealed JQ1 treatment to block a typical ES associated expression program. The effect on this expression program was mimicked by RNA interference with BRD3 or BRD4 expression, indicating that the EWS-FLI1 mediated expression profile is at least in part mediated via such epigenetic readers. Consequently, contact dependent and independent proliferation of different ES lines was strongly inhibited. Mechanistically, treatment of ES resulted in a partial arrest of the cell cycle as well as induction of apoptosis. Tumor development was suppressed dose dependently in a xeno-transplant model in immune deficient mice, overall indicating that ES may be susceptible to treatment with epigenetic inhibitors blocking BET bromodomain activity and the associated pathognomonic EWS-ETS transcriptional program.
authors.affiliation: Laboratory for Functional Genomics and Transplantation Biology, Children's Cancer Research Centre and Department of Pediatrics, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.|Comprehensive Cancer Center Munich (CCCM), Munich, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Hensel
authors.affiliation: Department of Oncology and Children's Research Center, University Children's Hospital, Zurich, Switzerland.
authors.forename: Chiara
authors.initials: C
authors.lastname: Giorgi
authors.affiliation: Laboratory for Functional Genomics and Transplantation Biology, Children's Cancer Research Centre and Department of Pediatrics, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.|Comprehensive Cancer Center Munich (CCCM), Munich, Germany.
authors.forename: Oxana
authors.initials: O
authors.lastname: Schmidt
authors.affiliation: Institute of Pathology, Helmholtz Zentrum München - German Research Center for Environmental Health (GmbH), Neuherberg, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Calzada-Wack
authors.affiliation: Institute of Pathology, Helmholtz Zentrum München - German Research Center for Environmental Health (GmbH), Neuherberg, Germany.
authors.forename: Frauke
authors.initials: F
authors.lastname: Neff
authors.affiliation: Institute of Pathology, Helmholtz Zentrum München - German Research Center for Environmental Health (GmbH), Neuherberg, Germany.|Institute of Laboratory Animal Science, University of Zurich, Zurich, Switzerland.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Buch
authors.affiliation: Department of Oncology and Children's Research Center, University Children's Hospital, Zurich, Switzerland.
authors.forename: Felix K
authors.initials: FK
authors.lastname: Niggli
authors.affiliation: Department of Oncology and Children's Research Center, University Children's Hospital, Zurich, Switzerland.
authors.forename: Beat W
authors.initials: BW
authors.lastname: Schäfer
authors.affiliation: Laboratory for Functional Genomics and Transplantation Biology, Children's Cancer Research Centre and Department of Pediatrics, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.|Comprehensive Cancer Center Munich (CCCM), Munich, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Burdach
authors.affiliation: Laboratory for Functional Genomics and Transplantation Biology, Children's Cancer Research Centre and Department of Pediatrics, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.|Comprehensive Cancer Center Munich (CCCM), Munich, Germany.
authors.forename: Günther H S
authors.initials: GH
authors.lastname: Richter
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001381:Azepines / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D058990:Molecular Targeted Therapy; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051789:Proto-Oncogene Protein c-fli-1 / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034802:RNA-Binding Protein EWS / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012512:Sarcoma, Ewing / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*; D014162:Transfection; D014230:Triazoles / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000092468:Bromodomain Containing Proteins
chemical_list: D000970:Antineoplastic Agents; D001381:Azepines; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D058539:Phosphatidylinositol 3-Kinase; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051789:Proto-Oncogene Protein c-fli-1; D034802:RNA-Binding Protein EWS; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D014230:Triazoles; C561695:(+)-JQ1 compound; C109106:BRD3 protein, human; D000092468:Bromodomain Containing Proteins; C441289:BRD4 protein, human; C106031:EWS-FLI fusion protein
keywords: BET bromodomains; Ewing sarcoma; JQ1; PI3K pathway; tumor growth