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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46 schema:keywords A673 Ewing's cell line
47 CDK2
48 Cdc6
49 DAX1
50 DAX1 function interference
51 DAX1 promoter
52 DAX1 targets
53 EWS/FLI1
54 EWS/FLI1 oncoprotein
55 Ewing Tumor Cells
56 Ewing cell lines
57 Ewing cells
58 Ewing family
59 Ewing tumors
60 Ewing's oncogenesis
61 FLI1
62 FLI1 oncoprotein
63 GGAA-rich region
64 Mcm10
65 RNA interference
66 RT-PCR
67 Skp2
68 analysis
69 approach
70 arrest
71 balanced chromosomal translocation
72 binding
73 cancer
74 capability
75 cell cycle progression
76 cell lines
77 cell-cycle progression regulator
78 cells
79 chimerical transcription factors
80 chromosomal translocations
81 direct target
82 direct transcriptional target
83 expression
84 expression profile analysis
85 factors
86 family
87 findings
88 form tumors
89 formation
90 function
91 function interference
92 functional genomic analysis
93 gene expression
94 gene expression profile analysis
95 genes
96 genomic analysis
97 growth arrest
98 hallmark
99 immunodeficient mice
100 importance
101 importance of DAX1
102 inducible model
103 interference
104 key players
105 lines
106 medium
107 mice
108 model
109 molecular hallmarks
110 new functions
111 new therapeutic approaches
112 nuclear receptors
113 oncogenesis
114 oncoprotein
115 orphan nuclear receptor
116 pathogenesis
117 pivotal role
118 players
119 possibility
120 presence
121 principal regulator
122 profile analysis
123 progression
124 progression regulator
125 promoter
126 quantitative RT-PCR
127 receptors
128 region
129 regulator
130 relevant targets
131 role
132 semisolid medium
133 study
134 target
135 therapeutic approaches
136 transcription factors
137 transcriptional targets
138 translocation
139 tumor cells
140 tumors
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