Oncogenic hijacking of a developmental transcription factor evokes therapeutic vulnerability for ROS-induction in Ewing sarcoma
Martin F. Orth,
Fabienne S. Wehweck,
Maximilian M. L. Knott,
Julia S. Gerke,
Michaela C. Baldauf,
Tilman L. B. Hölting,
James F. Amatruda,
Thomas G. P. Grünewald
Posted 14 Mar 2019
bioRxiv DOI: 10.1101/578666 (published DOI: 10.1038/s41467-020-16244-2)
Posted 14 Mar 2019
Ewing sarcoma (EwS) is an aggressive childhood cancer likely originating from mesenchymal stem cells or osteo-chondrogenic progenitors. It is characterized by fusion oncoproteins involving EWSR1 and variable members of the ETS-family of transcription factors (in 85% FLI1). EWSR1-FLI1 can induce target genes by using GGAA-microsatellites (mSats) as enhancers. Here, we show that EWSR1-FLI1 hijacks the developmental transcription factor SOX6 - a physiological driver of proliferation of osteo-chondrogenic progenitors - by binding to an intronic GGAA-mSat, which promotes EwS growth in vitro and in vivo. Through integration of transcriptome-profiling, published drug-screening data, and functional in vitro and in vivo experiments, we discovered that SOX6 interferes with the antioxidant system resulting in constitutively elevated reactive oxygen species (ROS) levels that create a therapeutic vulnerability toward the ROS-inducing drug Elesclomol. Collectively, our results exemplify how aberrant activation of a developmental transcription factor by a dominant oncogene can promote malignancy, but provide opportunities for targeted therapy.
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