ETS Proteins Bind with Glucocorticoid Receptors: Relevance for Treatment of Ewing Sarcoma

• Published in: Cell reports (Cambridge) Vol. 29; no. 1; pp. 104 - 117.e4
• Main Authors: Srivastava, Swati, Nataraj, Nishanth Belugali, Sekar, Arunachalam, Ghosh, Soma, Bornstein, Chamutal, Drago-Garcia, Diana, Roth, Lee, Romaniello, Donatella, Marrocco, Ilaria, David, Eyal, Gilad, Yuval, Lauriola, Mattia, Rotkopf, Ron, Kimchi, Adi, Haga, Yuya, Tsutsumi, Yasuo, Mirabeau, Olivier, Surdez, Didier, Zinovyev, Andrei, Delattre, Olivier, Kovar, Heinrich, Amit, Ido, Yarden, Yosef
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.10.2019; Cell Press; Elsevier
• Subjects: Animals; Bone Neoplasms - metabolism; cancer therapy; Cell Movement - physiology; Cell Nucleus - metabolism; Cell Proliferation - physiology; Ewing sarcoma; Female; Gene Expression Regulation, Neoplastic - physiology; glucocorticoid receptor; HEK293 Cells; Humans; metastasis; Mice; Mice, SCID; protein-fragment complementation assay; Proto-Oncogene Protein c-fli-1 - metabolism; Proto-Oncogene Proteins c-ets - metabolism; Receptors, Glucocorticoid - metabolism; RNA-Binding Protein EWS - metabolism; Sarcoma, Ewing - metabolism; cancer therapy; Ewing sarcoma; glucocorticoid receptor; protein-fragment complementation assay; metastasis
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2019.08.088

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. [Display omitted] •Glucocorticoids activate GR, an inducible TF regulating growth and metabolism•Protein complementation assays identified FLI1 and ERG as GR binders and activators•EWS-FLI1, a fusion protein, drives Ewing sarcoma (ES) and binds with activated GR•Pharmacological inhibition of GR activation retards progression in ES animal models 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.