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.
Highlights
Ewing sarcoma (ES) is an aggressive and poorly differentiated tumor, typically arising from bone and soft tissues in children and young adults
The mechanism by which EWS RNA binding protein 1 (EWSR1)-FLI1 contributes to tumorigenesis is complex since the fusion oncogene affects the cell in many different ways
The best known function of the EWSR1-FLI1 protein is that of an aberrant transcription factor
Summary
Ewing sarcoma (ES) is an aggressive and poorly differentiated tumor, typically arising from bone and soft tissues in children and young adults. ES tumors display a high degree of genomic stability with very few recurrent mutations besides the pathognomonic fusion, and are among the most genetically normal cancers [3,4,5] This strikingly unaltered somatic landscape highlights the role of EWSR1-FLI1 as the unique trigger of the oncogenic transformation in an otherwise yet unidentified cell-of-origin harboring key features that will likely contribute to the eventual development of ES. Data obtained by depleting EWSR1-FLI1 in ES cells revealed that many more genes resulted down-regulated by the fusion oncogene than up-regulated, suggesting that gene repression may be more prevalent than transcriptional activation [7] Many of these EWSR1-FLI1 repressed targets are divergent and highly dependent on the cellular background [8]. Since EWSR1-FLI1 directly binds to promoters of a small subset of repressed targets [7], the lack of consistency among the different sets of repressed genes is likely due to a variety of both direct and indirect mechanisms used by EWSR1-FLI1 for gene silencing
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