Targeting the epigenetic readers in Ewing Sarcoma inhibits the oncogenic transcription factor EWS/Fli1

Camille Jacques (1, 2) , François Lamoureux (1, 2) , Marc Baud 'Huin (2) , Lidia Rodriguez Calleja (3, 2) , Thibaut Quillard (1, 2) , Jérôme Amiaud (2) , Franck Tirode (4) , Françoise Rédini (2) , James E Bradner (5, 6) , Dominique Heymann (2, 7) , Benjamin Ory (1, 2)

1 Equipe Labellisée LIGUE 2012 [Nantes]
2 PhAN - Physiopathologie des Adaptations Nutritionnelles
3 Equipe LIGUE Nationale Contre le Cancer 2012
4 U830 - Unité de génétique et biologie des cancers
5 Department of Medical Oncology [Boston, MA, USA]
6 Department of Medicine [Boston, MA, USA]
7 CHU Nantes - Centre Hospitalier Universitaire de Nantes

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.

Mots clés: Ewing Sarcoma; JQ1; bromodomain; epigenetic; EWS/Fli1

Domaines: Médecine humaine et pathologie; Pédiatrie; Cancer; Rhumatologie et système ostéo-articulaire

Camille Jacques, François Lamoureux, Marc Baud 'Huin, Lidia Rodriguez Calleja, Thibaut Quillard, et al.. Targeting the epigenetic readers in Ewing Sarcoma inhibits the oncogenic transcription factor EWS/Fli1. Oncotarget, In press, 7 (17), pp.24125-40. ⟨10.18632/oncotarget.8214⟩. ⟨inserm-01702273⟩