DAX1, a direct target of EWS/FLI1 oncoprotein, is a principal regulator of cell-cycle progression in Ewing's tumor cells View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2008-06-30

AUTHORS

E García-Aragoncillo, J Carrillo, E Lalli, N Agra, G Gómez-López, Á Pestaña, J Alonso

ABSTRACT

The molecular hallmark of the Ewing's family of tumors is the presence of balanced chromosomal translocations, leading to the formation of chimerical transcription factors (that is, EWS/FLI1) that play a pivotal role in the pathogenesis of Ewing's tumors by deregulating gene expression. We have recently demonstrated that DAX1 (NR0B1), an orphan nuclear receptor that was not previously implicated in cancer, is induced by the EWS/FLI1 oncoprotein and is highly expressed in Ewing's tumors, suggesting that DAX1 is a biologically relevant target of EWS/FLI1-mediated oncogenesis. In this study we demonstrate that DAX1 is a direct transcriptional target of the EWS/FLI1 oncoprotein through its binding to a GGAA-rich region in the DAX1 promoter and show that DAX1 is a key player of EWS/FLI1-mediated oncogenesis. DAX1 silencing using an inducible model of RNA interference induces growth arrest in the A673 Ewing's cell line and severely impairs its capability to grow in semisolid medium and form tumors in immunodeficient mice. Gene expression profile analysis demonstrated that about 10% of the genes regulated by EWS/FLI1 in Ewing's cells are DAX1 targets, confirming the importance of DAX1 in Ewing's oncogenesis. Functional genomic analysis, validated by quantitative RT–PCR, showed that genes implicated in cell-cycle progression, such as CDK2, CDC6, MCM10 or SKP2 were similarly regulated by EWS/FLI1 and DAX1. These findings indicate that DAX1 is important in the pathogenesis of the Ewing's family of tumors, identify new functions for DAX1 as a cell-cycle progression regulator and open the possibility to new therapeutic approaches based on DAX1 function interference. More... »

PAGES

6034-6043

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/onc.2008.203

DOI

http://dx.doi.org/10.1038/onc.2008.203

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1044394606

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/18591936


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39 schema:description The molecular hallmark of the Ewing's family of tumors is the presence of balanced chromosomal translocations, leading to the formation of chimerical transcription factors (that is, EWS/FLI1) that play a pivotal role in the pathogenesis of Ewing's tumors by deregulating gene expression. We have recently demonstrated that DAX1 (NR0B1), an orphan nuclear receptor that was not previously implicated in cancer, is induced by the EWS/FLI1 oncoprotein and is highly expressed in Ewing's tumors, suggesting that DAX1 is a biologically relevant target of EWS/FLI1-mediated oncogenesis. In this study we demonstrate that DAX1 is a direct transcriptional target of the EWS/FLI1 oncoprotein through its binding to a GGAA-rich region in the DAX1 promoter and show that DAX1 is a key player of EWS/FLI1-mediated oncogenesis. DAX1 silencing using an inducible model of RNA interference induces growth arrest in the A673 Ewing's cell line and severely impairs its capability to grow in semisolid medium and form tumors in immunodeficient mice. Gene expression profile analysis demonstrated that about 10% of the genes regulated by EWS/FLI1 in Ewing's cells are DAX1 targets, confirming the importance of DAX1 in Ewing's oncogenesis. Functional genomic analysis, validated by quantitative RT–PCR, showed that genes implicated in cell-cycle progression, such as CDK2, CDC6, MCM10 or SKP2 were similarly regulated by EWS/FLI1 and DAX1. These findings indicate that DAX1 is important in the pathogenesis of the Ewing's family of tumors, identify new functions for DAX1 as a cell-cycle progression regulator and open the possibility to new therapeutic approaches based on DAX1 function interference.
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47 CDK2
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49 DAX1
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53 EWS/
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55 EWS/FLI1 oncoprotein
56 Ewing Tumor Cells
57 Ewing cell lines
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59 Ewing family
60 Ewing tumors
61 Ewing's oncogenesis
62 FLI1
63 FLI1 oncoprotein
64 GGAA-rich region
65 Mcm10
66 RNA interference
67 RT-PCR
68 Skp2
69 analysis
70 approach
71 arrest
72 balanced chromosomal translocation
73 binding
74 cancer
75 capability
76 cell lines
77 cell-cycle progression
78 cell-cycle progression regulator
79 cells
80 chimerical transcription factors
81 chromosomal translocations
82 direct target
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84 expression
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86 factors
87 family
88 findings
89 form tumors
90 formation
91 function
92 function interference
93 functional genomic analysis
94 gene expression
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96 genes
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99 hallmark
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101 importance
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103 inducible model
104 interference
105 key players
106 lines
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108 mice
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110 molecular hallmarks
111 new functions
112 new therapeutic approaches
113 nuclear receptors
114 oncogenesis
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117 pathogenesis
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121 presence
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123 profile analysis
124 progression
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126 promoter
127 quantitative RT-PCR
128 receptors
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136 therapeutic approaches
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