ETS Proteins Bind with Glucocorticoid Receptors: Relevance for Treatment of Ewing Sarcoma.
Animals
Bone Neoplasms
/ metabolism
Cell Movement
/ physiology
Cell Nucleus
/ metabolism
Cell Proliferation
/ physiology
Female
Gene Expression Regulation, Neoplastic
/ physiology
HEK293 Cells
Humans
Mice
Mice, SCID
Proto-Oncogene Protein c-fli-1
/ metabolism
Proto-Oncogene Proteins c-ets
/ metabolism
RNA-Binding Protein EWS
/ metabolism
Receptors, Glucocorticoid
/ metabolism
Sarcoma, Ewing
/ metabolism
Ewing sarcoma
cancer therapy
glucocorticoid receptor
metastasis
protein-fragment complementation assay
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
01 10 2019
01 10 2019
Historique:
received:
18
11
2018
revised:
06
02
2019
accepted:
27
08
2019
entrez:
3
10
2019
pubmed:
3
10
2019
medline:
18
9
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31577941
pii: S2211-1247(19)31150-7
doi: 10.1016/j.celrep.2019.08.088
pmc: PMC6899513
pii:
doi:
Substances chimiques
Proto-Oncogene Protein c-fli-1
0
Proto-Oncogene Proteins c-ets
0
RNA-Binding Protein EWS
0
Receptors, Glucocorticoid
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
104-117.e4Subventions
Organisme : European Research Council
ID : 740469
Pays : International
Informations de copyright
Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.
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