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

Malin Lindén1, Christer Thomsen1,2, Pernilla Grundevik1

  • 1Department of Pathology and Genetics, Sahlgrenska Cancer Center, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

EMBO Reports
|April 10, 2019
PubMed

Insights

The FET (FUS, EWSR1, TAF15) protein family interacts with the SWI/SNF chromatin remodeler. Oncogenic FET fusions deregulate this interaction, impacting gene expression and potentially driving cancer, offering new therapeutic targets.

Area of Science:

  • Molecular Biology
  • Oncology
  • Epigenetics

Background:

  • The human FET (FUS, EWSR1, TAF15) protein family are RNA-binding proteins involved in gene regulation.
  • FET gene fusions are oncogenic drivers in various sarcomas and leukemias.
  • The role of FET proteins in chromatin remodeling is not fully understood.

Purpose of the Study:

  • To investigate the interaction between FET proteins and the SWI/SNF chromatin remodeling complex.
  • To determine if this interaction is altered in FET-driven cancers.
  • To elucidate the functional consequences of deregulated FET-SWI/SNF interactions on gene expression and epigenetic modifications.

Main Methods:

  • Co-immunoprecipitation assays to assess protein-protein interactions.
  • Western blotting to detect protein levels and modifications.
  • Chromatin immunoprecipitation followed by sequencing (ChIP-seq) to analyze global H3K27 trimethylation.
  • RNA sequencing to assess gene expression changes.

Main Results:

  • Normal FET proteins and FET oncoproteins interact with the SWI/SNF complex.
  • FET oncoproteins exhibit enhanced and deregulated binding to SWI/SNF compared to normal FET proteins.
  • Forced expression of FET oncogenes alters global H3K27 trimethylation levels and gene expression patterns.
  • These alterations suggest a disrupted balance between SWI/SNF and Polycomb Repressive Complexes.

Conclusions:

  • Deregulation of SWI/SNF activity by FET fusion oncoproteins represents a unifying pathogenic mechanism in FET-driven tumors.
  • Targeting the FET-SWI/SNF interaction could offer novel therapeutic strategies for these cancers.
  • Understanding these molecular mechanisms is crucial for developing effective cancer therapies.
Keywords:
EWSR1‐FLI1FET proteinsFUS‐DDIT3SWI/SNF chromatin remodeling complexfusion oncogenes

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