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USP19 deubiquitinates EWS-FLI1 to regulate Ewing sarcoma growth
Ewing sarcoma is the second most common pediatric bone and soft tissue tumor presenting with an aggressive behavior and prevalence to metastasize. The diagnostic translocation t(22;11)(q24;12) leads to expression of the chimeric oncoprotein EWS-FLI1 which is uniquely expressed in all tumor cells and...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6353870/ https://www.ncbi.nlm.nih.gov/pubmed/30700749 http://dx.doi.org/10.1038/s41598-018-37264-5 |
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author | Gierisch, Maria E. Pedot, Gloria Walser, Franziska Lopez-Garcia, Laura A. Jaaks, Patricia Niggli, Felix K. Schäfer, Beat W. |
author_facet | Gierisch, Maria E. Pedot, Gloria Walser, Franziska Lopez-Garcia, Laura A. Jaaks, Patricia Niggli, Felix K. Schäfer, Beat W. |
author_sort | Gierisch, Maria E. |
collection | PubMed |
description | Ewing sarcoma is the second most common pediatric bone and soft tissue tumor presenting with an aggressive behavior and prevalence to metastasize. The diagnostic translocation t(22;11)(q24;12) leads to expression of the chimeric oncoprotein EWS-FLI1 which is uniquely expressed in all tumor cells and maintains their survival. Constant EWS-FLI1 protein turnover is regulated by the ubiquitin proteasome system. Here, we now identified ubiquitin specific protease 19 (USP19) as a regulator of EWS-FLI1 stability using an siRNA based screening approach. Depletion of USP19 resulted in diminished EWS-FLI1 protein levels and, vice versa, upregulation of active USP19 stabilized the fusion protein. Importantly, stabilization appears to be specific for the fusion protein as it could not be observed neither for EWSR1 nor for FLI1 wild type proteins even though USP19 binds to the N-terminal EWS region to regulate deubiquitination of both EWS-FLI1 and EWSR1. Further, stable shUSP19 depletion resulted in decreased cell growth and diminished colony forming capacity in vitro, and significantly delayed tumor growth in vivo. Our findings not only provide novel insights into the importance of the N-terminal EWSR1 domain for regulation of fusion protein stability, but also indicate that inhibition of deubiquitinating enzyme(s) might constitute a novel therapeutic strategy in treatment of Ewing sarcoma. |
format | Online Article Text |
id | pubmed-6353870 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-63538702019-01-31 USP19 deubiquitinates EWS-FLI1 to regulate Ewing sarcoma growth Gierisch, Maria E. Pedot, Gloria Walser, Franziska Lopez-Garcia, Laura A. Jaaks, Patricia Niggli, Felix K. Schäfer, Beat W. Sci Rep Article Ewing sarcoma is the second most common pediatric bone and soft tissue tumor presenting with an aggressive behavior and prevalence to metastasize. The diagnostic translocation t(22;11)(q24;12) leads to expression of the chimeric oncoprotein EWS-FLI1 which is uniquely expressed in all tumor cells and maintains their survival. Constant EWS-FLI1 protein turnover is regulated by the ubiquitin proteasome system. Here, we now identified ubiquitin specific protease 19 (USP19) as a regulator of EWS-FLI1 stability using an siRNA based screening approach. Depletion of USP19 resulted in diminished EWS-FLI1 protein levels and, vice versa, upregulation of active USP19 stabilized the fusion protein. Importantly, stabilization appears to be specific for the fusion protein as it could not be observed neither for EWSR1 nor for FLI1 wild type proteins even though USP19 binds to the N-terminal EWS region to regulate deubiquitination of both EWS-FLI1 and EWSR1. Further, stable shUSP19 depletion resulted in decreased cell growth and diminished colony forming capacity in vitro, and significantly delayed tumor growth in vivo. Our findings not only provide novel insights into the importance of the N-terminal EWSR1 domain for regulation of fusion protein stability, but also indicate that inhibition of deubiquitinating enzyme(s) might constitute a novel therapeutic strategy in treatment of Ewing sarcoma. Nature Publishing Group UK 2019-01-30 /pmc/articles/PMC6353870/ /pubmed/30700749 http://dx.doi.org/10.1038/s41598-018-37264-5 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Gierisch, Maria E. Pedot, Gloria Walser, Franziska Lopez-Garcia, Laura A. Jaaks, Patricia Niggli, Felix K. Schäfer, Beat W. USP19 deubiquitinates EWS-FLI1 to regulate Ewing sarcoma growth |
title | USP19 deubiquitinates EWS-FLI1 to regulate Ewing sarcoma growth |
title_full | USP19 deubiquitinates EWS-FLI1 to regulate Ewing sarcoma growth |
title_fullStr | USP19 deubiquitinates EWS-FLI1 to regulate Ewing sarcoma growth |
title_full_unstemmed | USP19 deubiquitinates EWS-FLI1 to regulate Ewing sarcoma growth |
title_short | USP19 deubiquitinates EWS-FLI1 to regulate Ewing sarcoma growth |
title_sort | usp19 deubiquitinates ews-fli1 to regulate ewing sarcoma growth |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6353870/ https://www.ncbi.nlm.nih.gov/pubmed/30700749 http://dx.doi.org/10.1038/s41598-018-37264-5 |
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