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Fusion protein-driv...
Fusion protein-driven IGF-IR/PI3K/AKT signals deregulate Hippo pathway promoting oncogenic cooperation of YAP1 and FUS-DDIT3 in myxoid liposarcoma
- Article/chapterEnglish2022
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2022-04-22
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Springer Science and Business Media LLC,2022
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LIBRIS-ID:oai:gup.ub.gu.se/317171
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https://gup.ub.gu.se/publication/317171URI
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https://doi.org/10.1038/s41389-022-00394-7DOI
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Subject category:art swepub-publicationtype
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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)
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Erkut, C.
(author)
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Heinst, L.
(author)
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Grunewald, I.
(author)
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Wardelmann, E.
(author)
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Kindler, T.
(author)
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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)
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Grunewald, T. G. P.
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Cidre-Aranaz, F.
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Trautmann, M.
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Frohling, S.
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Scholl, C.
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Hartmann, W.
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Göteborgs universitetSahlgrenska Centrum för Cancerforskning (SCCR)
(creator_code:org_t)
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In:Oncogenesis: Springer Science and Business Media LLC11:12157-9024
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Berthold, R.
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Isfort, I.
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Erkut, C.
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Heinst, L.
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Grunewald, I.
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Wardelmann, E.
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Kindler, T.
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Åman, Pierre, 19 ...
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Grunewald, T. G. ...
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Cidre-Aranaz, F.
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Trautmann, M.
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Frohling, S.
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Scholl, C.
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Hartmann, W.
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Cancer and Oncol ...
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Oncogenesis
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University of Gothenburg