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Targeting the EWS-ETS transcriptional program by BET bromodomain inhibition in Ewing sarcoma.
Oncotarget 7, 1451-1463 (2016)
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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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Bet Bromodomains ; Ewing Sarcoma ; Jq1 ; Pi3k Pathway ; Tumor Growth
ISSN (print) / ISBN
1949-2553
e-ISSN
1949-2553
Journal
OncoTarget
Quellenangaben
Volume: 7,
Issue: 2,
Pages: 1451-1463
Publisher
Impact Journals LLC
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Institute of Pathology (PATH)