RING1B contributes to Ewing sarcoma development by repressing the NaV1.6 sodium channel and the NF-κB pathway, independently of the fusion oncoprotein.

Hernández-Muñoz, InmaculadaFiguerola, ElisabethSanchez-Molina, SaraRodriguez García, EvaFernández Mariño, Ana Isabel, 1984-Pardo-Pastor, CarlosBahamonde Santos, María Isabel, 1972-Fernández-Fernández, José Manuel, 1967-García-Domínguez, Daniel J.Hontecillas-Prieto, LourdesLavarino, CinziaCarcaboso, Angel M.Torres, Carmen deTirado, Oscar M.Alava, Enrique deMora, Jaume2017-02-082017-02-082016Hernandez-Muñoz I, Figuerola E, Sanchez-Molina S, Rodriguez E, Fernández-Mariño AI, Pardo-Pastor C. et al. RING1B contributes to Ewing sarcoma development by repressing the NaV1.6 sodium channel and the NF-κB pathway, independently of the fusion oncoprotein. Oncotarget. 2016 Jul 19;7(29):46283-46300. DOI: 10.18632/oncotarget.100921949-2553http://hdl.handle.net/10230/28080Ewing sarcoma (ES) is an aggressive tumor defined by EWSR1 gene fusions that behave as an oncogene. Here we demonstrate that RING1B is highly expressed in primary ES tumors, and its expression is independent of the fusion oncogene. RING1B-depleted ES cells display an expression profile enriched in genes functionally involved in hematological development but RING1B depletion does not induce cellular differentiation. In ES cells, RING1B directly binds the SCN8A sodium channel promoter and its depletion results in enhanced Nav1.6 expression and function. The signaling pathway most significantly modulated by RING1B is NF-κB. RING1B depletion results in enhanced p105/p50 expression, which sensitizes ES cells to apoptosis by FGFR/SHP2/STAT3 blockade. Reduced NaV1.6 function protects ES cells from apoptotic cell death by maintaining low NF-κB levels. Our findings identify RING1B as a trait of the cell-of-origin and provide a potential targetable vulnerability.application/pdfeng© 2016 Hernandez-Muñoz et al. This is an open-access article distributed under the terms of the https://creativecommons.org/licenses/by/3.0/, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Sarcoma -- Aspectes genèticsRING1B contributes to Ewing sarcoma development by repressing the NaV1.6 sodium channel and the NF-κB pathway, independently of the fusion oncoprotein.info:eu-repo/semantics/articlehttp://dx.doi.org/10.18632/oncotarget.10092info:eu-repo/semantics/openAccess