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DAX1, a direct target of EWS/FLI1 oncoprotein, is a principal regulator of cell-cycle progression in Ewing's tumor cells.
Oncogene. 2008 Oct 09; 27(46):6034-43.O

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.

Authors+Show Affiliations

Departamento de Biología Molecular y Celular del Cáncer, Laboratorio de Genética y Patología Molecular de Tumores Sólidos Infantiles, Instituto de Investigaciones Biomédicas A Sols, CSIC-UAM, Madrid, Spain.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18591936

Citation

García-Aragoncillo, E, et al. "DAX1, a Direct Target of EWS/FLI1 Oncoprotein, Is a Principal Regulator of Cell-cycle Progression in Ewing's Tumor Cells." Oncogene, vol. 27, no. 46, 2008, pp. 6034-43.
García-Aragoncillo E, Carrillo J, Lalli E, et al. DAX1, a direct target of EWS/FLI1 oncoprotein, is a principal regulator of cell-cycle progression in Ewing's tumor cells. Oncogene. 2008;27(46):6034-43.
García-Aragoncillo, E., Carrillo, J., Lalli, E., Agra, N., Gómez-López, G., Pestaña, A., & Alonso, J. (2008). DAX1, a direct target of EWS/FLI1 oncoprotein, is a principal regulator of cell-cycle progression in Ewing's tumor cells. Oncogene, 27(46), 6034-43. https://doi.org/10.1038/onc.2008.203
García-Aragoncillo E, et al. DAX1, a Direct Target of EWS/FLI1 Oncoprotein, Is a Principal Regulator of Cell-cycle Progression in Ewing's Tumor Cells. Oncogene. 2008 Oct 9;27(46):6034-43. PubMed PMID: 18591936.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - DAX1, a direct target of EWS/FLI1 oncoprotein, is a principal regulator of cell-cycle progression in Ewing's tumor cells. AU - García-Aragoncillo,E, AU - Carrillo,J, AU - Lalli,E, AU - Agra,N, AU - Gómez-López,G, AU - Pestaña,A, AU - Alonso,J, Y1 - 2008/06/30/ PY - 2008/7/2/pubmed PY - 2008/11/13/medline PY - 2008/7/2/entrez SP - 6034 EP - 43 JF - Oncogene JO - Oncogene VL - 27 IS - 46 N2 - 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. SN - 1476-5594 UR - https://www.unboundmedicine.com/medline/citation/18591936/DAX1_a_direct_target_of_EWS/FLI1_oncoprotein_is_a_principal_regulator_of_cell_cycle_progression_in_Ewing's_tumor_cells_ L2 - https://doi.org/10.1038/onc.2008.203 DB - PRIME DP - Unbound Medicine ER -