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Acetylation Increases EWS-FLI1 DNA Binding and Transcriptional Activity
Ewing Sarcoma (ES) is associated with a balanced chromosomal translocation that in most cases leads to the expression of the oncogenic fusion protein and transcription factor EWS-FLI1. EWS-FLI1 has been shown to be crucial for ES cell survival and tumor growth. However, its regulation is still enigm...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Research Foundation
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3435532/ https://www.ncbi.nlm.nih.gov/pubmed/22973553 http://dx.doi.org/10.3389/fonc.2012.00107 |
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author | Schlottmann, Silke Erkizan, Hayriye V. Barber-Rotenberg, Julie S. Knights, Chad Cheema, Amrita Üren, Aykut Avantaggiati, Maria L. Toretsky, Jeffrey A. |
author_facet | Schlottmann, Silke Erkizan, Hayriye V. Barber-Rotenberg, Julie S. Knights, Chad Cheema, Amrita Üren, Aykut Avantaggiati, Maria L. Toretsky, Jeffrey A. |
author_sort | Schlottmann, Silke |
collection | PubMed |
description | Ewing Sarcoma (ES) is associated with a balanced chromosomal translocation that in most cases leads to the expression of the oncogenic fusion protein and transcription factor EWS-FLI1. EWS-FLI1 has been shown to be crucial for ES cell survival and tumor growth. However, its regulation is still enigmatic. To date, no functionally significant post-translational modifications of EWS-FLI1 have been shown. Since ES are sensitive to histone deacetylase inhibitors (HDI), and these inhibitors are advancing in clinical trials, we sought to identify if EWS-FLI1 is directly acetylated. We convincingly show acetylation of the C-terminal FLI1 (FLI1-CTD) domain, which is the DNA binding domain of EWS-FLI1. In vitro acetylation studies showed that acetylated FLI1-CTD has higher DNA binding activity than the non-acetylated protein. Over-expression of PCAF or treatment with HDI increased the transcriptional activity of EWS-FLI1, when co-expressed in Cos7 cells. However, our data that evaluates the acetylation of full-length EWS-FLI1 in ES cells remains unclear, despite creating acetylation specific antibodies to four potential acetylation sites. We conclude that EWS-FLI1 may either gain access to chromatin as a result of histone acetylation or undergo regulation by direct acetylation. These data should be considered when patients are treated with HDAC inhibitors. Further investigation of this phenomenon will reveal if this potential acetylation has an impact on tumor response. |
format | Online Article Text |
id | pubmed-3435532 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Frontiers Research Foundation |
record_format | MEDLINE/PubMed |
spelling | pubmed-34355322012-09-12 Acetylation Increases EWS-FLI1 DNA Binding and Transcriptional Activity Schlottmann, Silke Erkizan, Hayriye V. Barber-Rotenberg, Julie S. Knights, Chad Cheema, Amrita Üren, Aykut Avantaggiati, Maria L. Toretsky, Jeffrey A. Front Oncol Oncology Ewing Sarcoma (ES) is associated with a balanced chromosomal translocation that in most cases leads to the expression of the oncogenic fusion protein and transcription factor EWS-FLI1. EWS-FLI1 has been shown to be crucial for ES cell survival and tumor growth. However, its regulation is still enigmatic. To date, no functionally significant post-translational modifications of EWS-FLI1 have been shown. Since ES are sensitive to histone deacetylase inhibitors (HDI), and these inhibitors are advancing in clinical trials, we sought to identify if EWS-FLI1 is directly acetylated. We convincingly show acetylation of the C-terminal FLI1 (FLI1-CTD) domain, which is the DNA binding domain of EWS-FLI1. In vitro acetylation studies showed that acetylated FLI1-CTD has higher DNA binding activity than the non-acetylated protein. Over-expression of PCAF or treatment with HDI increased the transcriptional activity of EWS-FLI1, when co-expressed in Cos7 cells. However, our data that evaluates the acetylation of full-length EWS-FLI1 in ES cells remains unclear, despite creating acetylation specific antibodies to four potential acetylation sites. We conclude that EWS-FLI1 may either gain access to chromatin as a result of histone acetylation or undergo regulation by direct acetylation. These data should be considered when patients are treated with HDAC inhibitors. Further investigation of this phenomenon will reveal if this potential acetylation has an impact on tumor response. Frontiers Research Foundation 2012-09-07 /pmc/articles/PMC3435532/ /pubmed/22973553 http://dx.doi.org/10.3389/fonc.2012.00107 Text en Copyright © 2012 Schlottmann, Erkizan, Barber-Rotenberg, Knights, Cheema, Üren, Avantaggiati and Toretsky. http://www.frontiersin.org/licenseagreement This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc. |
spellingShingle | Oncology Schlottmann, Silke Erkizan, Hayriye V. Barber-Rotenberg, Julie S. Knights, Chad Cheema, Amrita Üren, Aykut Avantaggiati, Maria L. Toretsky, Jeffrey A. Acetylation Increases EWS-FLI1 DNA Binding and Transcriptional Activity |
title | Acetylation Increases EWS-FLI1 DNA Binding and Transcriptional Activity |
title_full | Acetylation Increases EWS-FLI1 DNA Binding and Transcriptional Activity |
title_fullStr | Acetylation Increases EWS-FLI1 DNA Binding and Transcriptional Activity |
title_full_unstemmed | Acetylation Increases EWS-FLI1 DNA Binding and Transcriptional Activity |
title_short | Acetylation Increases EWS-FLI1 DNA Binding and Transcriptional Activity |
title_sort | acetylation increases ews-fli1 dna binding and transcriptional activity |
topic | Oncology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3435532/ https://www.ncbi.nlm.nih.gov/pubmed/22973553 http://dx.doi.org/10.3389/fonc.2012.00107 |
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