Oncogenic ETS fusions deregulate E2F3 target genes in Ewing sarcoma and prostate cancer
- Sven Bilke1,
- Raphaela Schwentner2,
- Fan Yang1,
- Maximilian O. Kauer2,
- Gunhild Jug2,
- Robert L. Walker1,
- Sean Davis3,
- Yuelin J. Zhu3,
- Marbin Pineda1,
- Paul S. Meltzer1,4 and
- Heinrich Kovar2
- 1 National Cancer Institute;
- 2 Children's Cancer Research Institute, St. Anna Kinderkrebsforschung;
- 3 National Cancer Instiitute
- ↵* Corresponding author; email: pmeltzer{at}mail.nih.gov
Abstract
Deregulated E2F transcription factor activity occurs in the vast majority of human tumors and has been solidly implicated in disturbances of cell cycle control, proliferation and apoptosis. Aberrant E2F regulatory activity is often caused by impairment of control through pRB function but little is known about the interplay of other oncoproteins with E2F. Here we show that ETS transcription factor fusions resulting from disease driving rearrangements in Ewing sarcoma (ES) and prostate cancer (PC) are one such class of oncoproteins. We performed an integrative study of genome wide DNA-binding and transcription data in EWS/FLI1 expressing ES and TMPRSS2/ERG containing PC cells. Supported by promoter activity and mutation analyses, we demonstrate that a large fraction of E2F3 target genes are synergistically co-regulated by these aberrant ETS proteins. We propose that the oncogenic effect of ETS fusion oncoproteins is in part mediated by the disruptive effect of the E2F-ETS interaction on cell cycle control. Additionally, a detailed analysis of the regulatory targets of the characteristic EWS/FLI1 fusion in ES identifies two functionally distinct gene sets. While synergistic regulation in concert with E2F in the promoter of target-genes has a generally activating effect, EWS/FLI1 binding independent of E2F3 is predominantly associated with repressed differentiation genes. Thus, EWS/FLI1 appears to promote oncogenesis by simultaneously promoting cell proliferation and perturbing differentiation.
- Received October 26, 2012.
- Accepted August 6, 2013.
- © 2013, Published by Cold Spring Harbor Laboratory Press
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