The Cell Cycle Regulator CCDC6 Is a Key Target of RNA-Binding Protein EWS

Genetic translocation of EWSR1 to ETS transcription factor coding region is considered as primary cause for Ewing sarcoma. Previous studies focused on the biology of chimeric transcription factors formed due to this translocation. However, the physiological consequences of heterozygous EWSR1 loss in these tumors have largely remained elusive. Previously, we have identified various mRNAs bound to EWS using PAR-CLIP. In this study, we demonstrate CCDC6, a known cell cycle regulator protein, as a novel target regulated by EWS. siRNA mediated down regulation of EWS caused an elevated apoptosis in cells in a CCDC6-dependant manner. This effect was rescued upon re-expression of CCDC6. This study provides evidence for a novel functional link through which wild-type EWS operates in a target-dependant manner in Ewing sarcoma.

EWSR1基因与ETS转录因子编码区发生遗传易位，被认为是尤因肉瘤（Ewing sarcoma）的首要致病诱因。既往研究多聚焦于该易位所形成的嵌合转录因子的生物学特性。然而，此类肿瘤中EWSR1基因杂合缺失所带来的生理学效应，在很大程度上仍未被阐明。此前，我们团队已通过光活化核糖核苷增强交联免疫沉淀（PAR-CLIP）技术鉴定出多种与EWS蛋白结合的信使RNA（mRNA）。本研究中，我们证实了已知细胞周期调控蛋白CCDC6是EWS蛋白调控的全新靶标。经由小干扰RNA（siRNA）介导的EWS基因下调，会以CCDC6依赖的方式诱导细胞凋亡水平显著升高。若重新表达CCDC6，则可挽救该凋亡诱导效应。本研究为野生型EWS蛋白在尤因肉瘤中以靶标依赖的方式发挥功能提供了全新的功能性关联证据。