RING1B recruits EWSR1-FLI1 and cooperates in the remodeling of chromatin necessary for Ewing sarcoma tumorigenesis

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• dc.contributor.author Sánchez Molina, Sara
• dc.contributor.author Figuerola, Elisabeth
• dc.contributor.author Blanco, Enrique
• dc.contributor.author Sánchez Jiménez, María
• dc.contributor.author Táboas, Pablo
• dc.contributor.author Gómez, Soledad
• dc.contributor.author Ballaré, Cecilia Julia
• dc.contributor.author García-Domínguez, Daniel J.
• dc.contributor.author Prada, Estela
• dc.contributor.author Hontecillas-Prieto, Lourdes
• dc.contributor.author Carcaboso, Angel M.
• dc.contributor.author Tirado, Oscar M.
• dc.contributor.author Hernández Muñoz, María Inmaculada
• dc.contributor.author Alava, Enrique de
• dc.contributor.author Lavarino, Cinzia
• dc.contributor.author Di Croce, Luciano
• dc.contributor.author Mora, Jaume
• dc.date.accessioned 2020-11-17T06:54:54Z
• dc.date.available 2020-11-17T06:54:54Z
• dc.date.issued 2020
• dc.description.abstract Ewing sarcoma (EwS) is an aggressive tumor that affects adolescents and young adults. EwS is defined by a chromosomal translocation, EWSR1-FLI1 being the most common, that causes genome reprogramming through remodeling of enhancers. Here, we describe an unexpected function of RING1B, which is highly expressed in EwS. While retaining its repressive activity at Polycomb developmental regulated genes, RING1B colocalizes with EWSR1-FLI1 at active enhancers. We demonstrate that RING1B is necessary for the expression of key EWSR1-FLI1 targets by facilitating oncogene recruitment to their enhancers. Knockdown of RING1B impairs growth of tumor xenografts and expression of genes regulated by EWSR1-FLI1 bound enhancers. Pharmacological inhibition of AURKB with AZD1152 increases H2Aub levels causing down-regulation of RING1B/EWSR1-FLI1 common targets. Our findings demonstrate that RING1B is a critical modulator of EWSR1-FLI1-induced chromatin remodeling, and its inhibition is a potential therapeutic strategy for the treatment of these tumors.
• dc.description.sponsorship S.S.-M. and the project were supported by the Spanish Association Against Cancer (AECC) consolidated groups grant (GCB13131578) consortium. The project also had the support from the Asociacion Pablo Ugarte (APU). E.F.-B. was supported by the Spanish government grant, Instituto de Salud Carlos III (PI16/00245) to J.M. The work in the Di Croce laboratory was supported by grants from the Spanish of Economy, Industry and Competitiveness (MEIC) (BFU2016-75008-P), and Fundacion Vencer El Cancer (VEC).
• dc.format.mimetype application/pdf
• dc.identifier.citation Sánchez-Molina S, Figuerola-Bou E, Blanco E, Sánchez-Jiménez M, Táboas P, Gómez S, Ballaré C, García-Domínguez DJ, Prada E, Hontecillas-Prieto L, Carcaboso ÁM, Tirado ÓM, Hernández-Muñoz I, de Álava E, Lavarino C, Di Croce L, Mora J. RING1B recruits EWSR1-FLI1 and cooperates in the remodeling of chromatin necessary for Ewing sarcoma tumorigenesis. Sci Adv. 2020; 6(43):eaba3058. DOI: 10.1126/sciadv.aba3058
• dc.identifier.doi http://dx.doi.org/10.1126/sciadv.aba3058
• dc.identifier.issn 2375-2548
• dc.identifier.uri http://hdl.handle.net/10230/45785
• dc.language.iso eng
• dc.publisher American Association for the Advancement of Science (AAAS)
• dc.relation.ispartof Sci Adv. 2020; 6(43):eaba3058
• dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/BFU2016-75008-P
• dc.rights © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri https://creativecommons.org/licenses/by-nc/4.0/
• dc.title RING1B recruits EWSR1-FLI1 and cooperates in the remodeling of chromatin necessary for Ewing sarcoma tumorigenesis
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion