Functional Genomic Screening Reveals Splicing of the EWS-FLI1 Fusion Transcript as a Vulnerability in Ewing Sarcoma.
Functional Genomic Screening Reveals Splicing of the EWS-FLI1 Fusion Transcript as a Vulnerability in Ewing Sarcoma.
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DOI：
10.1016/j.celrep.2015.12.063
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发表时间：
2016-01-26
期刊：
影响因子：
8.8
通讯作者：
Caplen NJ
中科院分区：
文献类型：
--
作者：
Grohar PJ;Kim S;Rangel Rivera GO;Sen N;Haddock S;Harlow ML;Maloney NK;Zhu J;O'Neill M;Jones TL;Huppi K;Grandin M;Gehlhaus K;Klumpp-Thomas CA;Buehler E;Helman LJ;Martin SE;Caplen NJ
尤文肉瘤细胞的存活依赖于 EWS-FLI1 融合转录因子。通过 EWS-FLI1 活性测定和全基因组 RNAi 筛选，我们确定了处理 EWS-FLI1 前 mRNA 所需的蛋白质。我们发现，含有保留 EWSR1 外显子 8 的基因组断点的尤文肉瘤细胞需要 RNA 结合蛋白 HNRNPH1 来表达框内 EWS-FLI1。我们还证明了 EWS-FLI1 融合转录本对 U2 snRNP 成分 SF3B1 功能丧失的敏感性。 EWS-FLI1 转录本的剪接中断会改变 EWS-FLI1 蛋白表达和 EWS-FLI1 驱动的表达。我们的结果表明，EWS-FLI1 融合 RNA 的加工是尤文肉瘤细胞中潜在的可靶向脆弱性。
Ewing sarcoma cells depend on the EWS-FLI1 fusion transcription factor for cell survival. Using an assay of EWS-FLI1 activity and genome-wide RNAi screening, we have identified proteins required for the processing of the EWS-FLI1 pre-mRNA. We show Ewing sarcoma cells harboring a genomic breakpoint that retains exon 8 of EWSR1 require the RNA-binding protein HNRNPH1 to express in-frame EWS-FLI1. We also demonstrate the sensitivity of EWS-FLI1 fusion transcripts to the loss-of-function of the U2 snRNP component, SF3B1. Disrupted splicing of the EWS-FLI1 transcript alters EWS-FLI1 protein expression and EWS-FLI1 driven expression. Our results show that the processing of the EWS-FLI1 fusion RNA is a potentially targetable vulnerability in Ewing sarcoma cells.