Oncotarget

Research Papers:

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

Inmaculada Hernandez-Muñoz _, Elisabeth Figuerola, Sara Sanchez-Molina, Eva Rodriguez, Ana Isabel Fernández-Mariño, Carlos Pardo-Pastor, María Isabel Bahamonde, José M. Fernández-Fernández, Daniel J. García-Domínguez, Lourdes Hontecillas-Prieto, Cinzia Lavarino, Angel M. Carcaboso, Carmen de Torres, Oscar M. Tirado, Enrique de Alava and Jaume Mora

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Oncotarget. 2016; 7:46283-46300. https://doi.org/10.18632/oncotarget.10092

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Abstract

Inmaculada Hernandez-Muñoz1, Elisabeth Figuerola2,*, Sara Sanchez-Molina2,*, Eva Rodriguez2, Ana Isabel Fernández-Mariño3,6, Carlos Pardo-Pastor3, María Isabel Bahamonde3, José M. Fernández-Fernández3, Daniel J. García-Domínguez4, Lourdes Hontecillas-Prieto4, Cinzia Lavarino2, Angel M. Carcaboso2, Carmen de Torres2, Oscar M. Tirado5, Enrique de Alava4, Jaume Mora2

1Fundació Institut Hospital del Mar d’Investigacions Mèdiques (FIMIM), 08003-Barcelona, Spain

2Developmental Tumor Biology Laboratory, Department of Pediatric Hematology and Oncology, Hospital Sant Joan de Déu, 08950-Barcelona, Spain

3Laboratori de Fisiologia Molecular, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, 08003-Barcelona, Spain

4Department of Pediatric Hematology and Oncology, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocio/CSIC/Universidad de Sevilla, 41013-Seville, Spain

5Sarcoma Research Group, Laboratori d’Oncología Molecular, Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), L’Hospitalet de Llobregat, 08908-Barcelona, Spain

6Present Affiliation: Department of Neuroscience and Biomolecular Chemistry, School of Medicine and Public Health, University of Wisconsin, Madison-53705, USA

*These authors have contributed equally to this work

Correspondence to:

Inmaculada Hernandez-Muñoz, email: mhernandez@imim.es

Jaume Mora, email: Jmora@hsjdbcn.es

Keywords: RING1B, Ewing sarcoma, voltage-gated sodium channel, NF-κB, FGFR/SHP2/STAT3

Received: December 10, 2015    Accepted: May 28, 2016    Published: June 15, 2016

ABSTRACT

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.


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