ETS Proteins Bind with Glucocorticoid Receptors: Relevance for Treatment of Ewing Sarcoma
Swati Srivastava,
Nishanth Belugali Nataraj,
Arunachalam Sekar,
Soma Ghosh,
Chamutal Bornstein,
Diana Drago-Garcia,
Lee Roth,
Donatella Romaniello,
Ilaria Marrocco,
Eyal David,
Yuval Gilad,
Mattia Lauriola,
Ron Rotkopf,
Adi Kimchi,
Yuya Haga,
Yasuo Tsutsumi,
Olivier Mirabeau,
Didier Surdez,
Andrei Zinovyev,
Olivier Delattre,
Heinrich Kovar,
Ido Amit,
Yosef Yarden
Affiliations
Swati Srivastava
Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel
Nishanth Belugali Nataraj
Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel
Arunachalam Sekar
Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel
Soma Ghosh
Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel
Chamutal Bornstein
Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel
Diana Drago-Garcia
Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel
Lee Roth
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel
Donatella Romaniello
Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel
Ilaria Marrocco
Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel
Eyal David
Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel
Yuval Gilad
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel
Mattia Lauriola
Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy
Ron Rotkopf
Department of Biological Services, Weizmann Institute of Science, Rehovot 76100, Israel
Adi Kimchi
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel
Yuya Haga
Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel; Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan
Yasuo Tsutsumi
Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan; Global Center for Medical Engineering and Informatics, Osaka University, Japan
Olivier Mirabeau
PSL Research University, “Genetics and Biology of Cancers” Unit, INSERM U830 and Unité Génétique Somatique (UGS), Institut Curie Centre Hospitalier, Paris, France
Didier Surdez
PSL Research University, “Genetics and Biology of Cancers” Unit, INSERM U830 and Unité Génétique Somatique (UGS), Institut Curie Centre Hospitalier, Paris, France
Andrei Zinovyev
Institut Curie, PSL Research University, INSERM U900, Mines ParisTech, Paris, France
Olivier Delattre
PSL Research University, “Genetics and Biology of Cancers” Unit, INSERM U830 and Unité Génétique Somatique (UGS), Institut Curie Centre Hospitalier, Paris, France
Heinrich Kovar
Children’s Cancer Research Institute Vienna, St. Anna Kinderkrebsforschung and Department of Pediatrics, Medical University Vienna, Vienna, Austria
Ido Amit
Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel
Yosef Yarden
Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel; Corresponding author
Summary: The glucocorticoid receptor (GR) acts as a ubiquitous cortisol-dependent transcription factor (TF). To identify co-factors, we used protein-fragment complementation assays and found that GR recognizes FLI1 and additional ETS family proteins, TFs relaying proliferation and/or migration signals. Following steroid-dependent translocation of FLI1 and GR to the nucleus, the FLI1-specific domain (FLS) binds with GR and strongly enhances GR’s transcriptional activity. This interaction has functional consequences in Ewing sarcoma (ES), childhood and adolescence bone malignancies driven by fusions between EWSR1 and FLI1. In vitro, GR knockdown inhibited the migration and proliferation of ES cells, and in animal models, antagonizing GR (or lowering cortisol) retarded both tumor growth and metastasis from bone to lung. Taken together, our findings offer mechanistic rationale for repurposing GR-targeting drugs for the treatment of patients with ES. : The single oncogene of Ewing sarcoma (ES), a childhood cancer, encodes a FLI1 fusion protein. Srivastava et al. report physical interactions between the fusion protein and the glucocorticoid receptor. Drug-induced inhibition of these interactions retards the progression of ES in mouse models. Keywords: cancer therapy, Ewing sarcoma, glucocorticoid receptor, metastasis, protein-fragment complementation assay