通过对抗EWS-FLI1介导的增强子激活，ETV6在尤文肉瘤中表现出依赖性。
ETV6 dependency in Ewing sarcoma by antagonism of EWS-FLI1-mediated enhancer activation.
发表日期：2023 Feb
作者：
Yuan Gao, Xue-Yan He, Xiaoli S Wu, Yu-Han Huang, Shushan Toneyan, Taehoon Ha, Jonathan J Ipsaro, Peter K Koo, Leemor Joshua-Tor, Kelly M Bailey, Mikala Egeblad, Christopher R Vakoc
来源：
NATURE CELL BIOLOGY
摘要：
EWS-FLI1融合癌蛋白失去调节转录作用，引发儿童肿瘤伊万氏肉瘤。本文中，我们使用基于领域的CRISPR筛选技术，证明转录抑制剂ETV6是该肿瘤中的一个独特依赖因子。通过生化分析和表观遗传学研究，我们展示ETV6与富含短GGAA重复序列的选择性DNA元素竞争结合。当禁用ETV6时，EWS-FLI1取代并过度激活这些顺式作用元素，促进间充质分化，并将SOX11作为关键下游靶点。我们还展示通过使用优势干扰肽抑制ETV6，模拟这些效应并抑制伊万氏肉瘤在体内的生长。这些发现揭示了通过基因组占据重编程来靶向ETV6作为消除EWS-FLI1癌蛋白的策略。©2023年，作者（们），在Springer Nature有限公司的独家许可下。
The EWS-FLI1 fusion oncoprotein deregulates transcription to initiate the paediatric cancer Ewing sarcoma. Here we used a domain-focused CRISPR screen to implicate the transcriptional repressor ETV6 as a unique dependency in this tumour. Using biochemical assays and epigenomics, we show that ETV6 competes with EWS-FLI1 for binding to select DNA elements enriched for short GGAA repeat sequences. Upon inactivating ETV6, EWS-FLI1 overtakes and hyper-activates these cis-elements to promote mesenchymal differentiation, with SOX11 being a key downstream target. We show that squelching of ETV6 with a dominant-interfering peptide phenocopies these effects and suppresses Ewing sarcoma growth in vivo. These findings reveal targeting of ETV6 as a strategy for neutralizing the EWS-FLI1 oncoprotein by reprogramming of genomic occupancy.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.