Biochemical and Biophysical Research Communications, Vol.399, No.4, 705-710, 2010
EWS-FLI1 inhibits TNF alpha-induced NF kappa B-dependent transcription in Ewing sarcoma cells
Ewing sarcoma is primarily caused by a t(11;22) chromosomal translocation encoding the EWS-FLI1 fusion protein. To exert its oncogenic function, EWS-FLI1 acts as an aberrant transcription factor, broadly altering the gene expression profile of tumor cells. Nuclear factor-kappaB (NF kappa B) is a tightly regulated transcription factor controlling cell survival, proliferation and differentiation, as well as tumorigenesis. NF kappa B activity is very low in unstimulated Ewing sarcoma cells, but can be induced in response to tumor necrosis factor (TNF). We wondered whether NF kappa B activity could be modulated by EWS-FLI1 in Ewing sarcoma. Using a knockdown approach in Ewing sarcoma cells, we demonstrated that EWS-FLI1 has no influence on NF kappa B basal activity, but impairs TNF-induced NF kappa B-driven transcription, at least in part through inhibition of NF kappa B binding to DNA. We detected an in vivo physical interaction between the fusion protein and NF kappa B p65, which could mediate these effects. Our findings suggest that, besides directly controlling the activity of its primary target promoters, EWS-FLI1 can also indirectly influence gene expression in tumor cells by modulating the activity of key transcription factors such as NF kappa B. (C) 2010 Elsevier Inc. All rights reserved.