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Suppression of FOXO1 is responsible for a growth regulatory repressive transcriptional sub-signature of EWS-FLI1 in Ewing sarcoma
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Suppression of FOXO1 is responsible for a growth regulatory repressive transcriptional sub-signature of EWS-FLI1 in Ewing sarcoma
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Journal Article
Suppression of FOXO1 is responsible for a growth regulatory repressive transcriptional sub-signature of EWS-FLI1 in Ewing sarcoma
2014
Overview
The Ewing sarcoma (ES) EWS-FLI1 chimeric oncoprotein is a prototypic aberrant ETS transcription factor with activating and repressive regulatory functions. We report that EWS-FLI1-repressed promoters are enriched in forkhead box (FOX) recognition motifs, and identify FOXO1 as a EWS-FLI1-suppressed regulator orchestrating a major subset of EWS-FLI1-repressed genes. In addition to FOXO1 regulation by direct promoter binding of EWS-FLI1, its subcellular localization and activity is regulated by cyclin-dependent kinase 2- and AKT-mediated phosphorylation downstream of EWS-FLI1. Restoration of nuclear FOXO1 expression in ES cells impaired proliferation and significantly reduced clonogenicity. Gene-expression profiling revealed a significant overlap between EWS-FLI1-repressed and FOXO1-activated genes. As a proof of principle for a potential therapeutic application of our findings, the treatment of ES cell lines with methylseleninic acid (MSA) reactivated endogenous FOXO1 in the presence of EWS-FLI1 in a dose- and time-dependent manner and induced massive cell death dependent on FOXO1. In an orthotopic xenograft mouse model, MSA increased FOXO1 expression in the tumor paralleled by a significant decrease in ES tumor growth. FOXO1 reactivation by small molecules may therefore serve as a promising strategy for a future ES-specific therapy.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ Animals
/ Antineoplastic Agents - pharmacology
/ Bone Neoplasms - drug therapy
/ Cancer
/ Cyclin-Dependent Kinase 2 - metabolism
/ Forkhead Transcription Factors - genetics
/ Forkhead Transcription Factors - metabolism
/ Gene Expression Regulation, Neoplastic
/ Humans
/ Kinases
/ Medicine
/ Mice
/ Oncogene Proteins, Fusion - genetics
/ Oncogene Proteins, Fusion - metabolism
/ Oncology
/ Organoselenium Compounds - pharmacology
/ Original
/ Protein Processing, Post-Translational
/ Proto-Oncogene Protein c-fli-1 - genetics
/ Proto-Oncogene Protein c-fli-1 - metabolism
/ Proto-Oncogene Proteins c-akt - metabolism
/ RNA-Binding Protein EWS - genetics
/ RNA-Binding Protein EWS - metabolism
