Targeting the EWSR1-FLI1 Oncogene-Induced Protein Kinase PKC- Abolishes Ewing Sarcoma Growth in vivo
Résumé
Identification of druggable targets is a prerequisite for developing targeted therapies against
Ewing sarcoma. We report the identification of Protein Kinase C Beta (PRKCB) as a protein
specifically and highly expressed in Ewing sarcoma as compared to other pediatric cancers.
Its transcriptional activation is directly regulated by the EWSR1-FLI1 oncogene. Getting
insights in PRKCB activity we show that, together with PRKCA, it is responsible for the
phosphorylation of histone H3T6, allowing global maintenance of H3K4 trimethylation on a
variety of gene promoters. In the long term, PRKCB RNA interference induces apoptosis in
vitro. More importantly, in xenograft mice models, complete impairment of tumor engraftment
and even tumor regression were observed upon PRKCB inhibition, highlighting PRKCB as a
most valuable therapeutic target. Deciphering PRKCB roles in Ewing sarcoma using
expression profiling, we found a strong overlap with genes modulated by EWSR1-FLI1 and
an involvement of RPKCB in regulating crucial signaling pathways. Altogether, we show that
PRKCB may have two important independent functions and should be considered as highly
valuable for understanding Ewing sarcoma biology and as a promising target for new
therapeutic approaches in Ewing sarcoma.
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