Mutant FOXL2(C134W) hijacks SMAD4 and SMAD2/3 to drive adult granulosa cell tumors Journal Article

   


Authors: Weis-Banke, S. E.; Lerdrup, M.; Kleine-Kohlbrecher, D.; Mohammad, F.; Sidoli, S.; Jensen, O. N.; Yanase, T.; Nakamura, T.; Iwase, A.; Stylianou, A.; Abu-Rustum, N. R.; Aghajanian, C.; Soslow, R.; Da Cruz Paula, A.; Koche, R. P.; Weigelt, B.; Christensen, J.; Helin, K.; Cloos, P. A. C.
Article Title: Mutant FOXL2(C134W) hijacks SMAD4 and SMAD2/3 to drive adult granulosa cell tumors
Abstract: The mutant protein FOXL2(C134W) is expressed in at least 95% of adult-type ovarian granulosa cell tumors (AGCT) and is considered to be a driver of oncogenesis in this disease. However, the molecular mechanism by which FOXL2(C134W) contributes to tumorigenesis is not known. Here, we show that mutant FOXL2(C134W) acquires the ability to bind SMAD4, forming a FOXL2(C134W)/SMAD4/SMAD2/3 complex that binds a novel hybrid DNA motif AGHCAHAA, unique to the FOXL2(C134W) mutant. This binding induced an enhancer-like chromatin state, leading to transcription of nearby genes, many of which are characteristic of epithelial-to-mesenchymal transition. FOXL2(C134W) also bound hybrid loci in primary AGCT. Ablation of SMAD4 or SMAD2/3 resulted in strong reduction of FOXL2(C134W) binding at hybrid sites and decreased expression of associated genes. Accordingly, inhibition of TGF beta mitigated the transcriptional effect of FOXL2(C134W). Our results provide mechanistic insight into AGCT pathogenesis, identifying FOXL2(C134W) and its interaction with SMAD4 as potential therapeutic targets to this condition. Significance: FOXL2(C134W) hijacks SMAD4 and leads to the expression of genes involved in EMT, stemness, and oncogenesis in AGCT, making FOXL2(C134W) and the TGF beta pathway therapeutic targets in this condition.
Keywords: pathogenesis; mutations; expression; ovarian-cancer; free survival; dcc; foxl2; players
Journal Title: Cancer Research
Volume: 80
Issue: 17
ISSN: 0008-5472
Publisher: American Association for Cancer Research  
Date Published: 2020-09-01
Start Page: 3466
End Page: 3479
Language: English
ACCESSION: WOS:000567796800006
DOI: 10.1158/0008-5472.Can-20-0259
PROVIDER: wos
PUBMED: 32641411
PMCID: PMC8278322
Notes: Article -- Source: Wos
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MSK Authors
  1. Nadeem Abu-Rustum
    893 Abu-Rustum
  2. Robert Soslow
    797 Soslow
  3. Carol A Aghajanian
    613 Aghajanian
  4. Britta Weigelt
    642 Weigelt
  5. Richard Patrick Koche
    179 Koche
  6. Arnaud Fabian Da Cruz Paula
    146 Da Cruz Paula
  7. Kristian Helin
    35 Helin
  8. Anthe Alexia Stylianou
    24 Stylianou
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