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  • Berthold, R. (author)

Fusion protein-driven IGF-IR/PI3K/AKT signals deregulate Hippo pathway promoting oncogenic cooperation of YAP1 and FUS-DDIT3 in myxoid liposarcoma

  • Article/chapterEnglish2022

Publisher, publication year, extent ...

  • 2022-04-22
  • Springer Science and Business Media LLC,2022

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  • LIBRIS-ID:oai:gup.ub.gu.se/317171
  • https://gup.ub.gu.se/publication/317171URI
  • https://doi.org/10.1038/s41389-022-00394-7DOI

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  • Language:English

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  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • Myxoid liposarcoma (MLS) represents a common subtype of liposarcoma molecularly characterized by a recurrent chromosomal translocation that generates a chimeric FUS-DDIT3 fusion gene. The FUS-DDIT3 oncoprotein has been shown to be crucial in MLS pathogenesis. Acting as a transcriptional dysregulator, FUS-DDIT3 stimulates proliferation and interferes with adipogenic differentiation. As the fusion protein represents a therapeutically challenging target, a profound understanding of MLS biology is elementary to uncover FUS-DDIT3-dependent molecular vulnerabilities. Recently, a specific reliance on the Hippo pathway effector and transcriptional co-regulator YAP1 was detected in MLS; however, details on the molecular mechanism of FUS-DDIT3-dependent YAP1 activation, and YAP1 ' s precise mode of action remain unclear. In elaborate in vitro studies, employing RNA interference-based approaches, small-molecule inhibitors, and stimulation experiments with IGF-II, we show that FUS-DDIT3-driven IGF-IR/PI3K/AKT signaling promotes stability and nuclear accumulation of YAP1 via deregulation of the Hippo pathway. Co-immunoprecipitation and proximity ligation assays revealed nuclear co-localization of FUS-DDIT3 and YAP1/TEAD in FUS-DDIT3-expressing mesenchymal stem cells and MLS cell lines. Transcriptome sequencing of MLS cells demonstrated that FUS-DDIT3 and YAP1 co-regulate oncogenic gene signatures related to proliferation, cell cycle progression, apoptosis, and adipogenesis. In adipogenic differentiation assays, we show that YAP1 critically contributes to FUS-DDIT3-mediated adipogenic differentiation arrest. Taken together, our study provides mechanistic insights into a complex FUS-DDIT3-driven network involving IGF-IR/PI3K/AKT signals acting on Hippo/YAP1, and uncovers substantial cooperative effects of YAP1 and FUS-DDIT3 in the pathogenesis of MLS.

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  • Isfort, I. (author)
  • Erkut, C. (author)
  • Heinst, L. (author)
  • Grunewald, I. (author)
  • Wardelmann, E. (author)
  • Kindler, T. (author)
  • Åman, Pierre,1953Gothenburg University,Göteborgs universitet,Sahlgrenska Centrum för Cancerforskning (SCCR),Institutionen för biomedicin, avdelningen för laboratoriemedicin,Sahlgrenska Center for Cancer Research (SCCR),Department of Laboratory Medicine(Swepub:gu)xamapi (author)
  • Grunewald, T. G. P. (author)
  • Cidre-Aranaz, F. (author)
  • Trautmann, M. (author)
  • Frohling, S. (author)
  • Scholl, C. (author)
  • Hartmann, W. (author)
  • Göteborgs universitetSahlgrenska Centrum för Cancerforskning (SCCR) (creator_code:org_t)

Related titles

  • In:Oncogenesis: Springer Science and Business Media LLC11:12157-9024

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