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Genes regulated by JAK1/2 inhibitor ruxolitinib and myxoid liposarcoma-specific fusion onccogene FUS-DDIT3 in HT1080 cells.

ABSTRACT: Sarcomas and leukemias that are characterized by FET (FUS, EWSR1, TAF15) fusion oncogenes consist of more than 20 entities. Myxoid liposarcoma, one of the most common FET sarcoma types, is defined by the FUS-DDIT3 or the less common EWSR1-DDIT3 fusion oncogene. Previously, JAK-STAT signaling have been connected to cancer stem cell properties and chemotherapy resistance in myxoid liposarcoma, but the role of FUS-DDIT3 is not known. Therefore, we treated HT1080 fibrosarcoma cells expression FUS-DDIT3 with JAK1/2 inhibitor ruxolitinib and performed RNA sequencing of treated and control cells. Additionally, we analyzed native HT1080 cells to be able to compare the induced gene expression changes due to FUS-DDIT3 expression with those induced by JAK-STAT pathway inhibition.

ORGANISM(S): Homo sapiens

PROVIDER: GSE149650 | GEO | 2022/01/14

REPOSITORIES: GEO

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FET fusion oncoprotein-regulated genes in HT1080 cell line

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2019-03-13 | PXD012680 | Pride

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2023-12-31 | GSE230773 | GEO

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

Project description: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.

2022-03-28 | GSE184436 | GEO

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2022-04-18 | GSE179720 | GEO

Genes regulated by JAK1/2 inhibitor ruxolitinib and myxoid liposarcoma-specific fusion onccogene FUS-DDIT3 in HT1080 cells.

Project description:Genes regulated by JAK1/2 inhibitor ruxolitinib and myxoid liposarcoma-specific fusion onccogene FUS-DDIT3 in HT1080 cells.

| PRJNA629539 | ENA

The FUS-DDIT3 fusion oncoprotein inhibits BAF complex targeting and activity in myxoid liposarcoma

Project description:The FUS-DDIT3 fusion oncoprotein inhibits BAF complex targeting and activity in myxoid liposarcoma

| PRJNA744758 | ENA

Bromodomain and extraterminal proteins foster the core transcriptional regulatory programs and confer vulnerability in liposarcoma (ChIP-Seq)

Project description:Purpose: Identification of core transcriptional regulatory programs and bromodomain and extraterminal (BET) protein dependency in liposarcoma (LPS) Methods: ChIP-seq and RNA-seq were performed on LPS cells. Antibodies against H3K27ac, H3K4me1, H3K4me3, RNA-Pol2, BRD2, BRD3, BRD4, FOSL2, pan-RUNX, and DDIT3 (FUS-DDIT3) were used for ChIP-seq assays. The transcriptome responses of LPS141 and MLS402 cells to OTX015 and ARV-825 were compared. Result: We generated genome-wide chromatin-state maps of LPS cells. By charting the super-enhancer structures, we identify a bromodomain and extraterminal (BET) protein-cooperated FUS-DDIT3 function in myxoid LPS and a BET protein-dependent core transcriptional regulatory circuitry consisting of FOSL2, MYC, and RUNX1 in de-differentiated LPS. This study also provides a framework for discovering and targeting of core oncogenic transcriptional programs.

2019-04-01 | GSE111253 | GEO

Bromodomain and extraterminal proteins foster the core transcriptional regulatory programs and confer vulnerability in liposarcoma (RNA-Seq)

2019-04-01 | GSE111252 | GEO

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