期刊
EMBO REPORTS
卷 20, 期 5, 页码 -出版社
WILEY
DOI: 10.15252/embr.201845766
关键词
EWSR1-FLI1; FET proteins; FUS-DDIT3; fusion oncogenes; SWI; SNF chromatin remodeling complex
资金
- Swedish Cancer Society [CAN2015/7130, 2016/438]
- Swedish government
- ALF [ALFGBG-722211, 716321]
- Knut and Alice Wallenberg Foundation
- Wallenberg Centre for molecular and translational medicine at University of Gothenburg
- Swedish Research Council [2017-01392]
- VINNOVA
- Swedish Society for Medical Research
- Assar Gabrielssons Foundation
- BioCARE National Strategic Research
- Swedish Childhood Cancer Foundation [PR2017-0043]
- Swedish Society of Medicine
- Wilhelm and Martina Lundgren Foundation for Scientific Research
- Johan Jansson Foundation for Cancer Research
Members of the human FET family of RNA-binding proteins, comprising FUS, EWSR1, and TAF15, are ubiquitously expressed and engage at several levels of gene regulation. Many sarcomas and leukemias are characterized by the expression of fusion oncogenes with FET genes as 5 partners and alternative transcription factor-coding genes as 3 partners. Here, we report that the N terminus of normal FET proteins and their oncogenic fusion counterparts interact with the SWI/SNF chromatin remodeling complex. In contrast to normal FET proteins, increased fractions of FET oncoproteins bind SWI/SNF, indicating a deregulated and enhanced interaction in cancer. Forced expression of FET oncogenes caused changes of global H3K27 trimethylation levels, accompanied by altered gene expression patterns suggesting a shift in the antagonistic balance between SWI/SNF and repressive polycomb group complexes. Thus, deregulation of SWI/SNF activity could provide a unifying pathogenic mechanism for the large group of tumors caused by FET fusion oncoproteins. These results may help to develop common strategies for therapy.
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