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Títol:
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RING1B contributes to Ewing sarcoma development by repressing the NaV1.6 sodium channel and the NF-κB pathway, independently of the fusion oncoprotein.
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Autor/a:
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Hernández-Muñoz, Inmaculada; Figuerola, Elisabeth; Sanchez-Molina, Sara; Rodriguez García, Eva; Fernández Mariño, Ana Isabel, 1984-; Pardo-Pastor, Carlos; Bahamonde Santos, María Isabel, 1972-; Fernández-Fernández, José Manuel, 1967-; García-Domínguez, Daniel J.; Hontecillas-Prieto, Lourdes; Lavarino, Cinzia; Carcaboso, Angel M.; Torres, Carmen de; Tirado, Oscar M.; Alava, Enrique de; Mora, Jaume
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Abstract:
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Ewing 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. |
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Abstract:
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This work was supported by the Xarxa de Bancs de Tumors de Catalunya sponsored by Pla Director d’Oncologia de Catalunya and by grants from ISCIII-FEDER (PS09/00973; RIC RD12/0042/0014, Red HERACLES), Ministerio de Economía y Competitividad (MEC) (SAF2012-31089 and SAF2015-69762-R), FEDER Funds and by the Asociación Española Contra el Cáncer (AECC). E.Á.’s lab is supported by the AECC, MECFEDER (RD12/0036/0017, PT13/0010/0056, RTC-2014- 2102-1, ISCIII Sara Borrell CD06/00001, PI12/03102, PI14/01466), the European FP7 Projects EuroSARC (FP7- HEALTH-2011-two-stage, Project 278742 EUROSARC), Euroewing (FP7-HEALTH.2013.2.4.1-1, Project 602856), Fundación Memoria de DM Solorzano Barruso, Fundación Cris contra el Cáncer, Pablo Ugarte Foundation, and Fundación M. García Estrada. O.M.T. is funded by ISCIIIFEDER (CES12/021) and the AECC. AMC is funded by the European FP7 projects (FP7/2007-2013) under a Marie Curie International Reintegration Grant (PIRG- 08- GA-2010-276998) and ISCIII-FEDER (CP13/00189). The Ewing group at the Developmental Tumor Biology Laboratory, Hospital Sant Joan de Déu, is supported by the AECC and the generous donations from Pablo Ugarte Foundation. |
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Matèries:
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-Sarcoma -- Aspectes genètics |
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Drets:
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© 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.
https://creativecommons.org/licenses/by/3.0/
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Tipus de document:
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Article
Article - Versió publicada |
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Publicat per:
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