FET family fusion oncoproteins target the SWI/SNF chromatin remodeling complex

• Published in: EMBO reports 2019-05, Vol.20 (5), p.n/a
• Main Authors: Lindén, Malin, Thomsen, Christer, Grundevik, Pernilla, Jonasson, Emma, Andersson, Daniel, Runnberg, Rikard, Dolatabadi, Soheila, Vannas, Christoffer, Luna Santamarίa, Manuel, Fagman, Henrik, Ståhlberg, Anders, Åman, Pierre
• Format: Article
• Language: English
• Subjects: Binding sites; Cancer; Cell Line, Tumor; Chromatin - genetics; Chromatin - metabolism; Chromatin Assembly and Disassembly - genetics; Chromatin remodeling; Chromosomal Proteins, Non-Histone - genetics; Chromosomal Proteins, Non-Histone - metabolism; Deregulation; EMBO03; EMBO09; EMBO44; EWSR1-FLI1; FET proteins; FLI-1 protein; FUS-DDIT3; fusion oncogenes; Gene expression; Gene Expression Regulation - genetics; Gene regulation; Genes; Humans; Leukemia; Medical Genetics; Medicinsk genetik; Methylation; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Oncogene Proteins - genetics; Oncogene Proteins - metabolism; Oncoproteins; Polycomb group proteins; Polycomb-Group Proteins - genetics; Polycomb-Group Proteins - metabolism; Proteins; Ribonucleic acid; RNA; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; Scientific Report; Scientific Reports; SWI/SNF chromatin remodeling complex; Tumors
• ISSN: 1469-221X; 1469-3178
• DOI: 10.15252/embr.201845766

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. Synopsis N‐terminal parts of FET proteins and their oncogenic fusion variants interact with the SWI/SNF chromatin remodeling complex. Deregulation of SWI/SNF is a unifying pathogenic mechanism for tumors caused by FET fusion oncoproteins. FET oncoproteins show increased binding to SWI/SNF, indicating deregulated interactions in cancer. Normal and oncogenic FET proteins do not compete for binding, suggesting they interact with different variants of SWI/SNF or with distinct binding sites. Forced expression of FET oncogenes causes increased global H3K27 trimethylation. Graphical Abstract N‐terminal parts of FET proteins and their oncogenic fusion variants interact with the SWI/SNF chromatin remodeling complex. Deregulation of SWI/SNF is a unifying pathogenic mechanism for tumors caused by FET fusion oncoproteins.