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| Status |
Public on Dec 08, 2015 |
| Title |
Targeting the EWS/ETS transcriptional program by BET bromodomain inhibition in Ewing sarcoma |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
|
| Summary |
Ewing sarcomas (ES) are highly malignant, osteolytic bone or soft tissue tumors, which are characterized by early metastasis into lung and bone. 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. Microarray analysis further revealed JQ1 treatment to block a typical ES associated expression program. The effect on this expression program could be 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 in ES.
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| Overall design |
Ewing sarcoma cell lines A673 and TC-71 were treated for 48 hours with 2 microM JQ1 or DMSO control.
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| Contributor(s) |
Hensel T, Giorgi C, Schmidt O, Buch T, Burdach S, Schäfer B, Richter GH |
| Citation(s) |
26623725 |
| Submission date |
Sep 02, 2015 |
| Last update date |
Jul 26, 2018 |
| Contact name |
Guenther HS Richter |
| E-mail(s) |
guenther.richter@charite.de
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| Organization name |
Charité - Universitätsmedizin Berlin
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| Department |
Department of Pediatrics, Division of Oncology and Hematology
|
| Street address |
Augustenburger Platz 1
|
| City |
Berlin |
| ZIP/Postal code |
D-13353 |
| Country |
Germany |
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| Platforms (1) |
| GPL6244 |
[HuGene-1_0-st] Affymetrix Human Gene 1.0 ST Array [transcript (gene) version] |
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| Samples (4)
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| Relations |
| BioProject |
PRJNA294622 |
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