USP19 deubiquitinates EWS-FLI1 to regulate Ewing sarcoma growth

Abstract 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...

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Autores principales:	Maria E. Gierisch, Gloria Pedot, Franziska Walser, Laura A. Lopez-Garcia, Patricia Jaaks, Felix K. Niggli, Beat W. Schäfer
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2019
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/a3adb4d3106e433a8db0de295f5c3477
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spelling	oai:doaj.org-article:a3adb4d3106e433a8db0de295f5c34772021-12-02T15:09:47ZUSP19 deubiquitinates EWS-FLI1 to regulate Ewing sarcoma growth10.1038/s41598-018-37264-52045-2322https://doaj.org/article/a3adb4d3106e433a8db0de295f5c34772019-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-37264-5https://doaj.org/toc/2045-2322Abstract 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.Maria E. GierischGloria PedotFranziska WalserLaura A. Lopez-GarciaPatricia JaaksFelix K. NiggliBeat W. SchäferNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 9, Iss 1, Pp 1-12 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Maria E. Gierisch Gloria Pedot Franziska Walser Laura A. Lopez-Garcia Patricia Jaaks Felix K. Niggli Beat W. Schäfer USP19 deubiquitinates EWS-FLI1 to regulate Ewing sarcoma growth
description	Abstract 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	article
author	Maria E. Gierisch Gloria Pedot Franziska Walser Laura A. Lopez-Garcia Patricia Jaaks Felix K. Niggli Beat W. Schäfer
author_facet	Maria E. Gierisch Gloria Pedot Franziska Walser Laura A. Lopez-Garcia Patricia Jaaks Felix K. Niggli Beat W. Schäfer
author_sort	Maria E. Gierisch
title	USP19 deubiquitinates EWS-FLI1 to regulate Ewing sarcoma growth
title_short	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_sort	usp19 deubiquitinates ews-fli1 to regulate ewing sarcoma growth
publisher	Nature Portfolio
publishDate	2019
url	https://doaj.org/article/a3adb4d3106e433a8db0de295f5c3477
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USP19 deubiquitinates EWS-FLI1 to regulate Ewing sarcoma growth

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