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

• Verfasst von: Berthold, Ruth [VerfasserIn]
• Verfasst von: Isfort, Ilka [VerfasserIn]
• Verfasst von: Erkut, Cihan [VerfasserIn]
• Verfasst von: Heinst, Lorena [VerfasserIn]
• Verfasst von: Grünewald, Inga [VerfasserIn]
• Verfasst von: Wardelmann, Eva [VerfasserIn]
• Verfasst von: Kindler, Thomas [VerfasserIn]
• Verfasst von: Åman, Pierre [VerfasserIn]
• Verfasst von: Grünewald, Thomas G. P. [VerfasserIn]
• Verfasst von: Cidre-Aranaz, Florencia [VerfasserIn]
• Verfasst von: Trautmann, Marcel [VerfasserIn]
• Verfasst von: Fröhling, Stefan [VerfasserIn]
• Verfasst von: Scholl, Claudia [VerfasserIn]
• Verfasst von: Hartmann, Wolfgang [VerfasserIn]
• Titel: Fusion protein-driven IGF-IR/PI3K/AKT signals deregulate Hippo pathway promoting oncogenic cooperation of YAP1 and FUS-DDIT3 in myxoid liposarcoma
• Verf.angabe: Ruth Berthold, Ilka Isfort, Cihan Erkut, Lorena Heinst, Inga Grünewald, Eva Wardelmann, Thomas Kindler, Pierre Åman, Thomas G. P. Grünewald, Florencia Cidre-Aranaz, Marcel Trautmann, Stefan Fröhling, Claudia Scholl and Wolfgang Hartmann
• E-Jahr: 2022
• Jahr: 22 April 2022
• Umfang: 12 S.
• Fussnoten: Gesehen am 14.09.2022
• Titel Quelle: Enthalten in: Oncogenesis
• Ort Quelle: [Erscheinungsort nicht ermittelbar] : Nature Publ., 2012
• Jahr Quelle: 2022
• Band/Heft Quelle: 11(2022), 1, Artikel-ID 20, Seite 1-12
• ISSN Quelle: 2157-9024
• DOI: doi:10.1038/s41389-022-00394-7
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Growth factor signalling
• Sach-SW: Molecular biology
• Sach-SW: Oncogenes
• Sach-SW: Sarcoma
• K10plus-PPN: 1816623652

Abstract

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.