Cover Image

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...

Full description

Saved in:
Bibliographic Details
Main Authors: Berthold, Ruth (Author) , Isfort, Ilka (Author) , Erkut, Cihan (Author) , Heinst, Lorena (Author) , Grünewald, Inga (Author) , Wardelmann, Eva (Author) , Kindler, Thomas (Author) , Åman, Pierre (Author) , Grünewald, Thomas G. P. (Author) , Cidre-Aranaz, Florencia (Author) , Trautmann, Marcel (Author) , Fröhling, Stefan (Author) , Scholl, Claudia (Author) , Hartmann, Wolfgang (Author)
Format: Article (Journal)
Language:English
Published: 22 April 2022
In: Oncogenesis
Year: 2022, Volume: 11, Issue: 1, Pages: 1-12
ISSN:2157-9024
DOI:10.1038/s41389-022-00394-7
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1038/s41389-022-00394-7
Verlag, lizenzpflichtig, Volltext: https://www.nature.com/articles/s41389-022-00394-7
Get full text
Author Notes: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
Description
Summary: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.
Item Description:Gesehen am 14.09.2022
Physical Description:Online Resource
ISSN:2157-9024
DOI:10.1038/s41389-022-00394-7

Similar Items