Suppression of FOXO1 is responsible for a growth regulatory repressive transcriptional sub-signature of EWS-FLI1 in Ewing sarcoma View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2013-09-02

AUTHORS

S Niedan, M Kauer, D N T Aryee, R Kofler, R Schwentner, A Meier, U Pötschger, U Kontny, H Kovar

ABSTRACT

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. More... »

PAGES

3927-3938

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/onc.2013.361

DOI

http://dx.doi.org/10.1038/onc.2013.361

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1000488571

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/23995784


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42 schema:description 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.
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54 FOXO1
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59 addition
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61 binding
62 cell death
63 cell lines
64 cells
65 chimeric oncoprotein
66 clonogenicity
67 cyclin-dependent kinase 2
68 death
69 decrease
70 direct promoter binding
71 dose
72 endogenous FoxO1
73 expression
74 factors
75 findings
76 function
77 gene expression profiling
78 genes
79 growth
80 kinase 2
81 lines
82 localization
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84 manner
85 massive cell death
86 methylseleninic acid
87 model
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89 motif
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92 oncoprotein
93 orthotopic xenograft mouse model
94 overlap
95 phosphorylation
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97 presence
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106 reactivation
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108 regulation
109 regulator
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111 restoration
112 sarcoma
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115 small molecules
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