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The myxoid liposarcoma FUS-DDIT3 fusion oncoprotein deregulates NF-kappaB target genes by interaction with NFKBIZ

M Göransson1, M K Andersson, C Forni

  • 1Lundberg Laboratory for Cancer Research (LLCR), Department of Pathology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.

Oncogene
|October 14, 2008
PubMed

Insights

The FUS-DDIT3 fusion oncogene drives myxoid/round cell liposarcomas by upregulating IL8. This oncogene interacts with NFKBIZ, a nuclear factor, to deregulate NF-kappaB-controlled genes, contributing to cancer development.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • FUS, EWSR1, and TAF15 genes are implicated in tumor-specific fusion oncogenes.
  • The FUS-DDIT3 fusion oncogene, arising from t(12;16), initiates myxoid/round cell liposarcomas (MLS/RCLS).

Purpose of the Study:

  • To investigate the mechanism by which FUS-DDIT3 induces IL8 expression.
  • To explore the interaction between FUS-DDIT3 and the nuclear factor-kappaB (NF-kappaB) pathway.

Main Methods:

  • Chromatin immunoprecipitation (ChIP) to assess FUS-DDIT3 binding to the IL8 promoter.
  • Expression studies analyzing the IL8 promoter activity.
  • Immunoprecipitation and colocalization experiments to study protein interactions.

Main Results:

  • FUS-DDIT3 binds to the IL8 promoter and activates its expression, requiring the N-terminal FUS region.
  • FUS-DDIT3 interacts with the nuclear factor NFKBIZ, specifically binding its C-terminal.
  • Upregulation of additional NF-kappaB-controlled genes was observed in FUS-DDIT3-expressing cells, inducible by NFKBIZ.

Conclusions:

  • FUS-DDIT3 deregulates specific NF-kappaB-controlled genes via interaction with NFKBIZ.
  • This mechanism contributes to the oncogenic activity of FUS-DDIT3 in MLS/RCLS.
  • Similar pathways may be involved in other FUS, EWSR1, and TAF15-driven malignancies.

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