飞行1
增强子
生物
转录因子
癌症研究
重编程
染色质
融合蛋白
ETV6
细胞生物学
分子生物学
DNA
遗传学
基因
染色体易位
重组DNA
作者
Yuan Gao,Xue‐Yan He,Xiaoli Wu,Yuhan Huang,Shushan Toneyan,Taehoon Ha,Jonathan J. Ipsaro,Peter K. Koo,Leemor Joshua‐Tor,Kelly M. Bailey,Mikala Egeblad,Christopher R. Vakoc
标识
DOI:10.1038/s41556-022-01060-1
摘要
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. Independent but complementary studies from Vakoc and Stegmaier identify and characterize a role for ETV6 in counteracting the transcriptional activity of EWS-FLI1 during Ewing sarcoma development, which may be targeted for therapeutic benefits.
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