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The Transcription Factor FEZF1, a Direct Target of EWSR1-FLI1 in Ewing Sarcoma Cells, Regulates the Expression of Neural-Specific Genes

SIMPLE SUMMARY: Ewing sarcoma is a rare pediatric tumor characterized by chromosomal translocations that give rise to aberrant chimeric transcription factors (e.g., EWSR1-FLI1). EWSR1-FLI1 defines a specific transcriptomic profile in Ewing sarcoma cells, which determines the tumorigenesis process. O...

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Autores principales: García-García, Laura, Fernández-Tabanera, Enrique, Cervera, Saint T., Melero-Fernández de Mera, Raquel M., Josa, Santiago, González-González, Laura, Rodríguez-Martín, Carlos, Grünewald, Thomas G. P., Alonso, Javier
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8616448/
https://www.ncbi.nlm.nih.gov/pubmed/34830820
http://dx.doi.org/10.3390/cancers13225668
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author García-García, Laura
Fernández-Tabanera, Enrique
Cervera, Saint T.
Melero-Fernández de Mera, Raquel M.
Josa, Santiago
González-González, Laura
Rodríguez-Martín, Carlos
Grünewald, Thomas G. P.
Alonso, Javier
author_facet García-García, Laura
Fernández-Tabanera, Enrique
Cervera, Saint T.
Melero-Fernández de Mera, Raquel M.
Josa, Santiago
González-González, Laura
Rodríguez-Martín, Carlos
Grünewald, Thomas G. P.
Alonso, Javier
author_sort García-García, Laura
collection PubMed
description SIMPLE SUMMARY: Ewing sarcoma is a rare pediatric tumor characterized by chromosomal translocations that give rise to aberrant chimeric transcription factors (e.g., EWSR1-FLI1). EWSR1-FLI1 defines a specific transcriptomic profile in Ewing sarcoma cells, which determines the tumorigenesis process. Our study focused on the identification of transcription factors regulated by EWSR1-FLI1. FEZF1 (FEZ family zinc finger protein 1), a transcription factor involved in neural cell identity, was identified as one of the most strongly upregulated genes by EWSR1-FLI1. Functional studies were carried out to characterize the involvement of FEZF1 in Ewing sarcoma pathogenesis. As a result, the inhibition of FEZF1 diminished clonogenicity and cell proliferation in three Ewing sarcoma cell lines. Transcriptomic analysis revealed several neural-specific genes transcriptionally regulated by FEZF1 and concomitantly regulated by EWSR1-FLI1, which could explain the neural-like phenotype observed in several Ewing sarcoma cell lines and tumors. ABSTRACT: Ewing sarcoma is a rare pediatric tumor characterized by chromosomal translocations that give rise to aberrant chimeric transcription factors (e.g., EWSR1-FLI1). EWSR1-FLI1 promotes a specific cellular transcriptional program. Therefore, the study of EWSR1-FLI1 target genes is important to identify critical pathways involved in Ewing sarcoma tumorigenesis. In this work, we focused on the transcription factors regulated by EWSR1-FLI1 in Ewing sarcoma. Transcriptomic analysis of the Ewing sarcoma cell line A673 indicated that one of the genes more strongly upregulated by EWSR1-FLI1 was FEZF1 (FEZ family zinc finger protein 1), a transcriptional repressor involved in neural cell identity. The functional characterization of FEZF1 was performed in three Ewing sarcoma cell lines (A673, SK-N-MC, SK-ES-1) through an shRNA-directed silencing approach. FEZF1 knockdown inhibited clonogenicity and cell proliferation. Finally, the analysis of the FEZF1-dependent expression profile in A673 cells showed several neural genes regulated by FEZF1 and concomitantly regulated by EWSR1-FLI1. In summary, FEZF1 is transcriptionally regulated by EWSR1-FLI1 in Ewing sarcoma cells and is involved in the regulation of neural-specific genes, which could explain the neural-like phenotype observed in several Ewing sarcoma tumors and cell lines.
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spelling pubmed-86164482021-11-26 The Transcription Factor FEZF1, a Direct Target of EWSR1-FLI1 in Ewing Sarcoma Cells, Regulates the Expression of Neural-Specific Genes García-García, Laura Fernández-Tabanera, Enrique Cervera, Saint T. Melero-Fernández de Mera, Raquel M. Josa, Santiago González-González, Laura Rodríguez-Martín, Carlos Grünewald, Thomas G. P. Alonso, Javier Cancers (Basel) Article SIMPLE SUMMARY: Ewing sarcoma is a rare pediatric tumor characterized by chromosomal translocations that give rise to aberrant chimeric transcription factors (e.g., EWSR1-FLI1). EWSR1-FLI1 defines a specific transcriptomic profile in Ewing sarcoma cells, which determines the tumorigenesis process. Our study focused on the identification of transcription factors regulated by EWSR1-FLI1. FEZF1 (FEZ family zinc finger protein 1), a transcription factor involved in neural cell identity, was identified as one of the most strongly upregulated genes by EWSR1-FLI1. Functional studies were carried out to characterize the involvement of FEZF1 in Ewing sarcoma pathogenesis. As a result, the inhibition of FEZF1 diminished clonogenicity and cell proliferation in three Ewing sarcoma cell lines. Transcriptomic analysis revealed several neural-specific genes transcriptionally regulated by FEZF1 and concomitantly regulated by EWSR1-FLI1, which could explain the neural-like phenotype observed in several Ewing sarcoma cell lines and tumors. ABSTRACT: Ewing sarcoma is a rare pediatric tumor characterized by chromosomal translocations that give rise to aberrant chimeric transcription factors (e.g., EWSR1-FLI1). EWSR1-FLI1 promotes a specific cellular transcriptional program. Therefore, the study of EWSR1-FLI1 target genes is important to identify critical pathways involved in Ewing sarcoma tumorigenesis. In this work, we focused on the transcription factors regulated by EWSR1-FLI1 in Ewing sarcoma. Transcriptomic analysis of the Ewing sarcoma cell line A673 indicated that one of the genes more strongly upregulated by EWSR1-FLI1 was FEZF1 (FEZ family zinc finger protein 1), a transcriptional repressor involved in neural cell identity. The functional characterization of FEZF1 was performed in three Ewing sarcoma cell lines (A673, SK-N-MC, SK-ES-1) through an shRNA-directed silencing approach. FEZF1 knockdown inhibited clonogenicity and cell proliferation. Finally, the analysis of the FEZF1-dependent expression profile in A673 cells showed several neural genes regulated by FEZF1 and concomitantly regulated by EWSR1-FLI1. In summary, FEZF1 is transcriptionally regulated by EWSR1-FLI1 in Ewing sarcoma cells and is involved in the regulation of neural-specific genes, which could explain the neural-like phenotype observed in several Ewing sarcoma tumors and cell lines. MDPI 2021-11-12 /pmc/articles/PMC8616448/ /pubmed/34830820 http://dx.doi.org/10.3390/cancers13225668 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
García-García, Laura
Fernández-Tabanera, Enrique
Cervera, Saint T.
Melero-Fernández de Mera, Raquel M.
Josa, Santiago
González-González, Laura
Rodríguez-Martín, Carlos
Grünewald, Thomas G. P.
Alonso, Javier
The Transcription Factor FEZF1, a Direct Target of EWSR1-FLI1 in Ewing Sarcoma Cells, Regulates the Expression of Neural-Specific Genes
title The Transcription Factor FEZF1, a Direct Target of EWSR1-FLI1 in Ewing Sarcoma Cells, Regulates the Expression of Neural-Specific Genes
title_full The Transcription Factor FEZF1, a Direct Target of EWSR1-FLI1 in Ewing Sarcoma Cells, Regulates the Expression of Neural-Specific Genes
title_fullStr The Transcription Factor FEZF1, a Direct Target of EWSR1-FLI1 in Ewing Sarcoma Cells, Regulates the Expression of Neural-Specific Genes
title_full_unstemmed The Transcription Factor FEZF1, a Direct Target of EWSR1-FLI1 in Ewing Sarcoma Cells, Regulates the Expression of Neural-Specific Genes
title_short The Transcription Factor FEZF1, a Direct Target of EWSR1-FLI1 in Ewing Sarcoma Cells, Regulates the Expression of Neural-Specific Genes
title_sort transcription factor fezf1, a direct target of ewsr1-fli1 in ewing sarcoma cells, regulates the expression of neural-specific genes
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8616448/
https://www.ncbi.nlm.nih.gov/pubmed/34830820
http://dx.doi.org/10.3390/cancers13225668
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