Journal
ONCOTARGET
Volume 7, Issue 29, Pages 46283-46300Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.10092
Keywords
RING1B; Ewing sarcoma; voltage-gated sodium channel; NF-kappa B; FGFR/SHP2/STAT3
Categories
Funding
- Xarxa de Bancs de Tumors de Catalunya
- Pla Director d'Oncologia de Catalunya
- ISCIII-FEDER [PS09/00973, RIC RD12/0042/0014, CES12/021, CP13/00189]
- Ministerio de Economia y Competitividad (MEC) [SAF2012-31089, SAF2015-69762-R]
- FEDER Funds
- Asociacion Espanola Contra el Cancer (AECC)
- AECC
- MEC-FEDER [RD12/0036/0017, PT13/0010/0056, RTC-20142102-1, CD06/00001, PI12/03102, PI14/01466]
- European FP7 Projects EuroSARC (FP7HEALTH-two-stage) [278742]
- Euroewing [FP7-HEALTH.2013.2.4.1-1, 602856]
- Fundacion Memoria de DM Solorzano Barruso
- Fundacion Cris contra el Cancer
- Pablo Ugarte Foundation
- Fundacion M. Garcia Estrada
- European FP7 projects (FP7) under a Marie Curie International Reintegration Grant [PIRG08-GA-2010-276998]
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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-kappa B. RING1B depletion results in enhanced p105/p50 expression, which sensitizes ES cells to apoptosis by FGFR/ SHP2/STAT3 blockade. Reduced Na(V)1.6 function protects ES cells from apoptotic cell death by maintaining low NF-kappa B levels. Our findings identify RING1B as a trait of the cell-of-origin and provide a potential targetable vulnerability.
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