Oncotarget

Research Papers:

Targeting the EWS-ETS transcriptional program by BET bromodomain inhibition in Ewing sarcoma

Tim Hensel, Chiara Giorgi, Oxana Schmidt, Julia Calzada-Wack, Frauke Neff, Thorsten Buch, Felix K. Niggli, Beat W. Schäfer, Stefan Burdach and Günther H.S. Richter _

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Oncotarget. 2016; 7:1451-1463. https://doi.org/10.18632/oncotarget.6385

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Abstract

Tim Hensel1,2*, Chiara Giorgi3,*, Oxana Schmidt1,2, Julia Calzada-Wack4, Frauke Neff4, Thorsten Buch5,6, Felix K. Niggli3, Beat W. Schäfer3, Stefan Burdach1,2 and Günther H.S. Richter1,2

1 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

2 Comprehensive Cancer Center Munich (CCCM), Munich, Germany

3 Department of Oncology and Children’s Research Center, University Children’s Hospital, Zurich, Switzerland

4 Institute of Pathology, Helmholtz Zentrum München - German Research Center for Environmental Health (GmbH), Neuherberg, Germany

5 Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München, Munich, Germany

6 Institute of Laboratory Animal Science, University of Zurich, Zurich, Switzerland

* These authors are joint first authors. Results contain part of the doctoral theses work

Correspondence to:

Günther H. S. Richter, email:

Keywords: BET bromodomains, Ewing sarcoma, tumor growth, JQ1, PI3K pathway

Received: September 11, 2015 Accepted: November 16, 2015 Published: November 25, 2015

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.


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