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Targeting the EWSR1-FLI1 Oncogene-Induced Protein Kinase PKC- Abolishes Ewing Sarcoma Growth in vivo

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Surdez, Didier | Benetkiewicz, Magdalena | Perrin, V. | Han, Zhi-Yan | Pierron, Gaëlle | Ballet, Stelly | Lamoureux, François | Rédini, Françoise | Daudigeos-Dubus, Estelle | Geoerger, Birgit | Delattre, Olivier | Tirode, Franck

Edité par CCSD ; American Association for Cancer Research -

International audience. Identification of druggable targets is a prerequisite for developing targeted therapies againstEwing sarcoma. We report the identification of Protein Kinase C Beta (PRKCB) as a proteinspecifically and highly expressed in Ewing sarcoma as compared to other pediatric cancers.Its transcriptional activation is directly regulated by the EWSR1-FLI1 oncogene. Gettinginsights in PRKCB activity we show that, together with PRKCA, it is responsible for thephosphorylation of histone H3T6, allowing global maintenance of H3K4 trimethylation on avariety of gene promoters. In the long term, PRKCB RNA interference induces apoptosis invitro. More importantly, in xenograft mice models, complete impairment of tumor engraftmentand even tumor regression were observed upon PRKCB inhibition, highlighting PRKCB as amost valuable therapeutic target. Deciphering PRKCB roles in Ewing sarcoma usingexpression profiling, we found a strong overlap with genes modulated by EWSR1-FLI1 andan involvement of RPKCB in regulating crucial signaling pathways. Altogether, we show thatPRKCB may have two important independent functions and should be considered as highlyvaluable for understanding Ewing sarcoma biology and as a promising target for newtherapeutic approaches in Ewing sarcoma.

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