TY - JOUR
T1 - ETS Proteins Bind with Glucocorticoid Receptors
T2 - Relevance for Treatment of Ewing Sarcoma
AU - Srivastava, Swati
AU - Nataraj, Nishanth Belugali
AU - Sekar, Arunachalam
AU - Ghosh, Soma
AU - Bornstein, Chamutal
AU - Drago-Garcia, Diana
AU - Roth, Lee
AU - Romaniello, Donatella
AU - Marrocco, Ilaria
AU - David, Eyal
AU - Gilad, Yuval
AU - Lauriola, Mattia
AU - Rotkopf, Ron
AU - Kimchi, Adi
AU - Haga, Yuya
AU - Tsutsumi, Yasuo
AU - Mirabeau, Olivier
AU - Surdez, Didier
AU - Zinovyev, Andrei
AU - Delattre, Olivier
AU - Kovar, Heinrich
AU - Amit, Ido
AU - Yarden, Yosef
N1 - We thank Tomer Meir Salame and Kira Glatzel for help; Aykut Uren for guidance; Jefferey Toretsky and Peter Ambros for cell lines; and Yaacov Ben-David, Anne Gompel, and Andrew Cato for sharing reagents. This work was performed in the Marvin Tanner Laboratory for Research on Cancer. Y.Y. is the incumbent of the Harold and Zelda Goldenberg Professorial Chair in Molecular Cell Biology. Our studies are supported by the Israel Science Foundation (ISF; 280/15), the European Research Council (ERC; 740469), and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (AMRF; 12). Author Contributions S.S. and Y.Y. designed the experiments and wrote the manuscript. S.S., N.B.N., A.S., C.B., S.G., D.D.-G., L.R., D.R., I.M., Y.H., Y.G., and O.M. performed the experiments. R.R., E.D., O.M., D.S., A.Z., Y.T., O.D., and I.A. analyzed statistical and other data. M.L., A.K., I.A., and H.K. reviewed the manuscript.
PY - 2019/10/1
Y1 - 2019/10/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85072272041&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2019.08.088
DO - 10.1016/j.celrep.2019.08.088
M3 - مقالة
SN - 2211-1247
VL - 29
SP - 104
EP - 117
JO - Cell Reports
JF - Cell Reports
IS - 1
ER -