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Title

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

AuthorsHernández-Muñoz, Inmaculada; Figuerola, Elisabeth; Sánchez-Molina, Sara; Rodríguez, Eva; Fernández-Maríño, A. I.; Pardo-Pastor, Carlos; Bahamonde, María Isabel; Fernández-Fernández, J. M.; García-Domínguez, Daniel J.; Hontecillas-Prieto, Lourdes; Lavarino, Cinzia; Carcaboso, Ángel M.; Torres, Carmen de; Tirado, Óscar M.; Álava, Enrique de ; Mora, Jaume
KeywordsRING1B
Ewing sarcoma
Voltage-gated sodium channel
NF-κB
FGFR/SHP2/STAT3
Issue Date15-Jun-2016
PublisherImpact Journals
CitationOncotarget 7(29): 46283-46300 (2016)
AbstractEwing 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.
Publisher version (URL)https://doi.org/10.18632/oncotarget.10092
URIhttp://hdl.handle.net/10261/198065
DOI10.18632/oncotarget.10092
E-ISSN1949-2553
Appears in Collections:(IBIS) Artículos
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