Institut Curie, INSERM U830, Unité de Génétique et Biologie des Cancers, Institut Curie, Unité de génétique somatique, Paris, France.
Cancer Res. 2012 Sep 1;72(17):4494-503. doi: 10.1158/0008-5472.CAN-12-0371. Epub 2012 Aug 28.
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.
尤因肉瘤是一种罕见但侵袭性很强的疾病，多见于年轻人。这种癌症是由一种独特的嵌合融合致癌基因驱动的，但靶向治疗策略一直难以捉摸。在这里，我们报告了蛋白激酶 PKC-β（PRKCB）的鉴定，它是一种针对尤因肉瘤治疗的疾病特异性可用药靶。我们发现 PRKCB 的转录激活受驱动这种癌症的嵌合融合致癌基因 EWSR1-FLI1 的直接调控。PRKCB 磷酸化组蛋白 H3T6，以允许各种基因启动子处的 H3K4 三甲基化的全局维持。PRKCB 缺失在体外诱导细胞凋亡，并在体内防止肿瘤生长。基因表达谱分析显示，EWSR1-FLI1 和 PRKCB 调节关键信号通路的基因之间存在很强的重叠。总之，我们的研究结果为 PRKCB 作为尤因肉瘤有前途的治疗靶点提供了临床前概念验证。
