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
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.Ministerio de Economía y Competitividad SAF2012-31089 and SAF2015-69762-RMEC FEDER RD12/0036/0017, PT13/0010/0056, RTC-2014- 2102-1, ISCIII Sara Borrell CD06/00001, PI12/03102, PI14/01466European FP7 Projects EuroSARC FP7- HEALTH-2011-two-stage, Project 278742 EUROSARCEuroewing FP7-HEALTH.2013.2.4.1-1, Project 60285
