Didier Surdez,
Magdalena Benetkiewicz,
Virginie Perrin,
Zhi-Yan Han,
Ga€ Elle Pierron, Stelly Ballet,
François Lamoureux,
Françoise R Edini,
Anne-Val Erie Decouvelaere,
Estelle Daudigeos-Dubus,
Birgit Geoerger,
Gonzague De Pinieux,
Olivier Delattre,
Franck Tirode
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ABSTRACT: Ewing sarcoma is a rare but aggressive disease most common in young adults. This cancer is driven by a unique chimeric fusion oncogene but targeted strategies have been elusive. Here we report the identification of the protein kinase PKC-ß (PRKCB) as a disease-specific druggable target for treatment of Ewing sarcoma. We found that transcriptional activation of PRKCB was directly regulated by the chimeric fusion oncogene EWSR1-FLI1 that drives this cancer. PRKCB phosphorylated histone H3T6 to permit global maintenance of H3K4 trimethylation at a variety of gene promoters. PRKCB loss induced apoptosis in vitro and prevented tumor growth in vivo. Gene expression profiling revealed a strong overlap between genes modulated by EWSR1-FLI1 and PRKCB in regulating crucial signaling pathways. Taken together, our findings offer a preclinical proof-of-concept for PRKCB as a promising therapeutic target in Ewing sarcoma. Cancer Res; 72(17); 1–10. Ó2012 AACR.
Cancer Research 08/2012; 28. · 7.86 Impact Factor
