Abstract
Ewing Sarcoma is a rare bone and soft tissue malignancy affecting children and young adults. Chromosomal translocations in this cancer produce fusion oncogenes as characteristic molecular signatures of the disease. The most common case is the translocation t (11; 22) (q24;q12) which yields the EWS-Fli1 chimeric transcription factor. Finding a way to directly target EWS-Fli1 remains a central therapeutic approach to eradicate this aggressive cancer. Here we demonstrate that treating Ewing Sarcoma cells with JQ1(+), a BET bromodomain inhibitor, represses directly EWS-Fli1 transcription as well as its transcriptional program. Moreover, the Chromatin Immuno Precipitation experiments demonstrate for the first time that these results are a consequence of the depletion of BRD4, one of the BET bromodomains protein from the EWS-Fli1 promoter. In vitro, JQ1(+) treatment reduces the cell viability, impairs the cell clonogenic and the migratory abilities, and induces a G1-phase blockage as well as a time- and a dose-dependent apoptosis. Furthermore, in our in vivo model, we observed a tumor burden delay, an inhibition of the global vascularization and an increase of the mice overall survival. Taken together, our data indicate that inhibiting the BET bromodomains interferes with EWS-FLi1 transcription and could be a promising strategy in the Ewing tumors context.
Highlights
Ewing Sarcoma is the second most common bone cancer after Osteosarcoma
Taken together and considering the EWS-Fli1 oncogene addiction of the Ewing Sarcoma cells, our findings indicate that targeting the bromodomain and extraterminal domain (BET) bromodomain signaling pathway in Ewing tumor can effectively disrupt the progression of this cancer through transcriptional repression of its main oncogenic driver [43]
Ewing Sarcoma cell lines are sensitive to BET proteins inhibition therapy To directly assess the relevance of targeting BET bromodomain proteins signaling in Ewing Sarcoma disease, we first evaluated the messenger RNA expression level of BRD2, BRD3 and BRD4 in ten human Ewing Sarcoma cell lines
Summary
Ewing Sarcoma is the second most common bone cancer after Osteosarcoma It is an infrequent tumor, mostly affecting children and young adults, with a peak of incidence around 15 years [1]. The standard of care for young patients suffering from Ewing Sarcoma is based on a multimodal therapy including surgical resection associated with local radiotherapy and chemotherapy combination [1, 3,4,5]. This strategy has markedly improved the patient outcome worldwide, since the 5-year survival rates after treatment are currently around 60–70% for the localized forms. The unsatisfactory prognosis of such patients and the fact that the toxicity thresholds have already been achieved underscore the necessity to find novel therapeutic strategy
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