RT Journal Article
T1 RING1B contributes to Ewing sarcoma development by repressing the Na(V)1.6 sodium channel and the NF-kappa B pathway, independently of the fusion oncoprotein
A1 Hernandez-Munoz, Inmaculada
A1 Figuerola, Elisabeth
A1 Sanchez-Molina, Sara
A1 Rodriguez, Eva
A1 Isabel Fernandez-Marino, Ana
A1 Pardo-Pastor, Carlos
A1 Isabel Bahamonde, Maria
A1 Fernandez-Fernandez, Jose M.
A1 Garcia-Dominguez, Daniel J.
A1 Hontecillas-Prieto, Lourdes
A1 Lavarino, Cinzia
A1 Carcaboso, Angel M.
A1 de Torres, Carmen
A1 Tirado, Oscar M.
A1 de Alava, Enrique
A1 Mora, Jaume
K1 RING1B
K1 Ewing sarcoma
K1 voltage-gated sodium channel
K1 NF-kappa B
K1 FGFR/SHP2/STAT3
K1 Fibroblast-growth-factor
K1 Marrow stromal cells
K1 In-vivo
K1 Neuroectodermal tumors
K1 Neural differentiation
K1 Tyrosine-phosphatase
K1 Genomic landscape
K1 Histone h2a
K1 Stem-cells
K1 Family
AB 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.
PB Impact journals llc
YR 2016
FD 2016-07-19
LK http://hdl.handle.net/10668/19432
UL http://hdl.handle.net/10668/19432
LA en
DS RISalud
RD Apr 7, 2025