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 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.
Fundació Institut Hospital del Mar d'Investigacions Mèdiques (FIMIM), 08003-Barcelona, Spain.
Inmaculada
I
Hernandez-Muñoz
Developmental Tumor Biology Laboratory, Department of Pediatric Hematology and Oncology, Hospital Sant Joan de Déu, 08950-Barcelona, Spain.
Elisabeth
E
Figuerola
Developmental Tumor Biology Laboratory, Department of Pediatric Hematology and Oncology, Hospital Sant Joan de Déu, 08950-Barcelona, Spain.
Sara
S
Sanchez-Molina
Developmental Tumor Biology Laboratory, Department of Pediatric Hematology and Oncology, Hospital Sant Joan de Déu, 08950-Barcelona, Spain.
Eva
E
Rodriguez
Laboratori de Fisiologia Molecular, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, 08003-Barcelona, Spain.|Present Affiliation: Department of Neuroscience and Biomolecular Chemistry, School of Medicine and Public Health, University of Wisconsin, Madison-53705, USA.
Ana Isabel
AI
Fernández-Mariño
Laboratori de Fisiologia Molecular, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, 08003-Barcelona, Spain.
Carlos
C
Pardo-Pastor
Laboratori de Fisiologia Molecular, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, 08003-Barcelona, Spain.
María Isabel
MI
Bahamonde
Laboratori de Fisiologia Molecular, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, 08003-Barcelona, Spain.
José M
JM
Fernández-Fernández
Department of Pediatric Hematology and Oncology, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocio/CSIC/Universidad de Sevilla, 41013-Seville, Spain.
Daniel J
DJ
García-Domínguez
Department of Pediatric Hematology and Oncology, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocio/CSIC/Universidad de Sevilla, 41013-Seville, Spain.
Lourdes
L
Hontecillas-Prieto
Developmental Tumor Biology Laboratory, Department of Pediatric Hematology and Oncology, Hospital Sant Joan de Déu, 08950-Barcelona, Spain.
Cinzia
C
Lavarino
Developmental Tumor Biology Laboratory, Department of Pediatric Hematology and Oncology, Hospital Sant Joan de Déu, 08950-Barcelona, Spain.
Angel M
AM
Carcaboso
Developmental Tumor Biology Laboratory, Department of Pediatric Hematology and Oncology, Hospital Sant Joan de Déu, 08950-Barcelona, Spain.
Carmen
C
de Torres
Sarcoma Research Group, Laboratori d'Oncología Molecular, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, 08908-Barcelona, Spain.
Oscar M
OM
Tirado
Department of Pediatric Hematology and Oncology, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocio/CSIC/Universidad de Sevilla, 41013-Seville, Spain.
Enrique
E
de Alava
Developmental Tumor Biology Laboratory, Department of Pediatric Hematology and Oncology, Hospital Sant Joan de Déu, 08950-Barcelona, Spain.
Jaume
J
Mora
D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D062557:NAV1.6 Voltage-Gated Sodium Channel / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D063150:Polycomb Repressive Complex 1 / Q000378:metabolism*; D012512:Sarcoma, Ewing / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology; D014407:Tumor Cells, Cultured
D062557:NAV1.6 Voltage-Gated Sodium Channel; D016328:NF-kappa B; C100681:SCN8A protein, human; D063150:Polycomb Repressive Complex 1; C489841:RNF2 protein, human
Ewing sarcoma; FGFR/SHP2/STAT3; NF-κB; RING1B; voltage-gated sodium channel