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

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 g...

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Bibliographic Details
Published in:Oncotarget 2016-07, Vol.7 (29), p.46283-46300
Main Authors: Hernandez-Muñoz, Inmaculada, Figuerola, Elisabeth, Sanchez-Molina, Sara, Rodriguez, Eva, Fernández-Mariño, Ana Isabel, Pardo-Pastor, Carlos, Bahamonde, María Isabel, Fernández-Fernández, José M, García-Domínguez, Daniel J, Hontecillas-Prieto, Lourdes, Lavarino, Cinzia, Carcaboso, Angel M, de Torres, Carmen, Tirado, Oscar M, de Alava, Enrique, Mora, Jaume
Format: Article
Language:English
Subjects:
Aspectes genètics
Bone Neoplasms - genetics
Bone Neoplasms - metabolism
Bone Neoplasms - pathology
Humans
NAV1.6 Voltage-Gated Sodium Channel - metabolism
NF-kappa B - metabolism
Polycomb Repressive Complex 1 - metabolism
Research Paper
Sarcoma
Sarcoma, Ewing - genetics
Sarcoma, Ewing - metabolism
Sarcoma, Ewing - pathology
Signal Transduction - physiology
Tumor Cells, Cultured
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Summary: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.
ISSN:1949-2553
1949-2553
DOI:10.18632/oncotarget.10092