Fusion protein-driven IGF-IR/PI3K/AKT signals deregulate Hippo pathway promoting oncogenic cooperation of YAP1 and FUS-DDIT3 in myxoid liposarcoma
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...
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Dokumenttypen: | Artikel |
Medientypen: | Text |
Erscheinungsdatum: | 2022 |
Publikation in MIAMI: | 22.09.2023 |
Datum der letzten Änderung: | 22.09.2023 |
Angaben zur Ausgabe: | [Electronic ed.] |
Quelle: | Oncogenesis 11 (2022), 20, 1-12 |
Schlagwörter: | Growth factor signalling; Molecular biology; Oncogenes; Sarcoma |
Fachgebiet (DDC): | 610: Medizin und Gesundheit |
Lizenz: | CC BY 4.0 |
Sprache: | English |
Förderung: | Finanziert über die DEAL-Vereinbarung mit Wiley 2019-2022. Förderer: Deutsche Forschungsgemeinschaft / Projektnummer: 455323733 Förderer: Deutsche Forschungsgemeinschaft / Projektnummer: 398417454 |
Format: | PDF-Dokument |
URN: | urn:nbn:de:hbz:6-59908641614 |
Weitere Identifikatoren: | DOI: 10.17879/49918570477 |
Permalink: | https://nbn-resolving.de/urn:nbn:de:hbz:6-59908641614 |
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Onlinezugriff: | 10.1038_s41389-022-00394-7.pdf |
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.