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PAX3-FOXO1 suppresses cellular senescence through RASSF4-mediated restraint of the mammalian Hippo/MST1 pathway

ABSTRACT: Alveolar rhabdomyosarcoma (aRMS) is an aggressive sarcoma of skeletal muscle characterized by expression of the PAX3-FOXO1 fusion gene. Despite its discovery over almost 20 years ago, PAX3-FOXO1 remains an enigmatic tumor driver. Previously, we reported that PAX3-FOXO1 supports aRMS initiation by enabling bypass of cellular senescence. Here, we show that bypass occurs in part by PAX3-FOXO1-mediated upregulation of RASSF4, a Ras-association domain family (RASSF) member, which then suppresses the evolutionarily conserved mammalian Hippo/Mst1 pathway. RASSF4 loss-of-function activates Hippo/Mst1 and inhibits downstream YAP, causing aRMS cell cycle arrest and senescence. This is the first evidence for an oncogenic role for RASSF4, and a novel mechanism for Hippo signaling suppression in human cancer. Human skeletal muscle myoblasts (HSMMs) were retrovirally transduced with either an empty vector (Vp, pK1) or PAX3-FOXO1 (PFp, pK1-PAX3-FOXO1) and selected on puromycin. Presenescent (presen) cells were harvested before the senescence checkpoint. Since cells expressing PAX3-FOXO1 can bypass the senescence checkpoint, postsenescent (postsen) cells expressing PAX3-FOXO1 were also harvested.

ORGANISM(S): Homo sapiens

PROVIDER: GSE40543 | GEO | 2014/05/15

SECONDARY ACCESSION(S): PRJNA174363

REPOSITORIES: GEO

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PAX3-FOXO1 suppresses cellular senescence through RASSF4-mediated restraint of the mammalian Hippo/MST1 pathway

Project description:Alveolar rhabdomyosarcoma (aRMS) is an aggressive sarcoma of skeletal muscle characterized by expression of the PAX3-FOXO1 fusion gene. Despite its discovery over almost 20 years ago, PAX3-FOXO1 remains an enigmatic tumor driver. Previously, we reported that PAX3-FOXO1 supports aRMS initiation by enabling bypass of cellular senescence. Here, we show that bypass occurs in part by PAX3-FOXO1-mediated upregulation of RASSF4, a Ras-association domain family (RASSF) member, which then suppresses the evolutionarily conserved mammalian Hippo/Mst1 pathway. RASSF4 loss-of-function activates Hippo/Mst1 and inhibits downstream YAP, causing aRMS cell cycle arrest and senescence. This is the first evidence for an oncogenic role for RASSF4, and a novel mechanism for Hippo signaling suppression in human cancer. Human skeletal muscle myoblasts (HSMMs) were retrovirally transduced with either an empty vector (Vp, pK1) or PAX3-FOXO1 (PFp, pK1-PAX3-FOXO1) and selected on puromycin. Presenescent (presen) cells were harvested before the senescence checkpoint. Since cells expressing PAX3-FOXO1 can bypass the senescence checkpoint, postsenescent (postsen) cells expressing PAX3-FOXO1 were also harvested. the gene expression affected by the introduction of PAX3-FOXO1

2014-05-15 | E-GEOD-40543 | biostudies-arrayexpress

Homo sapiens

Project description:PAX3-FOXO1 suppresses cellular senescence through RASSF4-mediated restraint of the mammalian Hippo/MST1 pathway

| PRJNA174363 | ENA

BioID HEK293T PAX3-FOXO1 proximity labelling

Project description:PAX3-FOXO1 is a fusion transcription factor that is the main driver of tumorigenesis leading to the development of alveolar rhabdomyosarcoma (aRMS). Since aRMS cells are addicted to PAX3-FOXO1 activity, the fusion protein also represents a major target for therapeutic interference, which is however challenging as transcription factors usually cannot be inhibited directly by small molecules. Hence, characterization of the biology of PAX3-FOXO1 might lead to the discovery of new possibilities for an indirect inhibition of its activity. Here, our goal was to characterize the proteomic neighborhood of PAX3-FOXO1 and to find candidates potentially affecting its activity and tumor cell viability. Towards this aim, we expressed BirA fused versions of PAX3-FOXO1 (N- and C-terminal) in HEK293T cells under presence of biotin. In the control setup, we expressed the BirA enzyme alone. After Streptavidin purification of biotinylated proteins, we performed mass spectrometry and quantified relative abundances compared to control conditions. This enabled us to determine PAX3-FOXO1 proximal proteins, which we investigated further in orthogonal endogenous systems.

2021-09-16 | PXD022187 | Pride

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Project description:Alveolar Rhabdomyosarcoma (ARMS) is the most aggressive subtype mainly caused by the expression of PAX3/7-FOXO1 oncoproteins Here, we show that G9a interacts with PAX3-FOXO1 and regulates its activity. In line with this, transcriptomic analysis by RNA-seq revealed that G9a depletion in RH41 cells induced transcriptional changes inversely correlated by those imposed by PAX3-FOXO1 expression. Overall, our results indicate that G9a promotes PAX3-FOXO1 stability, thus sustaining ARMS myoblastic state.

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Therapeutic targeting of ATR in alveolar rhabdomyosarcoma

Project description:Despite advances in multi-modal treatment approaches, clinical outcomes of patients suffering from PAX3-FOXO1 fusion oncogene-expressing alveolar rhabdomyosarcoma (ARMS) remain dismal. Here we show that PAX3-FOXO1-expressing ARMS cells are sensitive to pharmacological ataxia telangiectasia and Rad3 related protein (ATR) inhibition. Expression of PAX3-FOXO1 in muscle progenitor cells is not only sufficient to increase sensitivity to ATR inhibition, but PAX3-FOXO1-expressing rhabdomyosarcoma cells also exhibit increased sensitivity to structurally diverse inhibitors of ATR. Mechanistically, ATR inhibition leads to replication stress exacerbation, decreased BRCA1 phosphorylation and reduced homologous recombination-mediated DNA repair pathway activity. Consequently, ATR inhibitor treatment increases sensitivity of ARMS cells to PARP1 inhibition in vitro, and combined treatment with ATR and PARP1 inhibitors induces complete regression of primary patient-derived ARMS xenografts in vivo. Lastly, a genome-wide CRISPR activation screen (CRISPRa) in combination with transcriptional analyses of ATR inhibitor resistant ARMS cells identifies the RAS-MAPK pathway and its targets, the FOS gene family, as inducers of resistance to ATR inhibition. Our findings provide a rationale for upcoming biomarker-driven clinical trials of ATR inhibitors in patients suffering from ARMS.

2022-07-11 | PXD035131 | JPOST Repository

Identification of 17-DMAG as a novel KDM4B inhibitor for combination therapy [ChIP-seq]

Project description:Histone demethylases such as KDM4B play critical roles in oncogenic pathophysiology and, therefore may be effective targets for anticancer therapy. Using a TR-FRET demethylation screen assay, in combination with multiple orthogonal validation approaches, we identified geldanamycin and its analog 17-DMAG as novel KDM4B inhibitors. In addition, we found that these Hsp90 inhibitors effect increased degradation of the alveolar rhabdomyosarcoma (aRMS) driver oncoprotein PAX3-FOXO1 and induce the H3K9me3 and H3K36me3 at genomic loci of PAX3-FOXO1 targets. We found that as monotherapy 17-DMAG significantly inhibits expression of PAX3-FOXO1 target genes and multiple oncogenic pathways, induces a muscle differentiation signature, delays tumor growth and extends survival in aRMS xenograft mouse models. The combination of 17-DMAG with conventional chemotherapy significantly enhances therapeutic efficacy, indicating that targeting KDM4B in combination with chemotherapy may serve as a novel therapy to PAX3-FOXO1-positive aRMS.

2020-12-22 | GSE151493 | GEO

Transcription profiling of human embryonal rhabdomyosarcoma (EMRS) culture to identify PAX3-FKHR regulated genes differentially expressed between alveolar and embryonal rhabdomyosarcomas

Project description:The overall goal and objective is to study the degree to which PAX3-FKHR accounts for differences between ARMS and ERMS by expressing a construct (termed P3FK/ER) consisting of PAX3-FKHR joined to the estrogen receptor ligand binding domain in an ERMS cell culture system. Experiment Overall Design: In the study design, three populations of RD ERMS cells expressing P3FK/ER were treated with or without 30 nM 4-hydroxytamoxifen and three control populations transduced with vector only (pK1) were similarly treated.

2009-03-14 | E-GEOD-15103 | biostudies-arrayexpress

Regulatory landscape fusion in rhabdomyosarcoma by interactions between the PAX3 promoter and FOXO1 regulatory elements

Project description:Results: Using a combination of 4C-seq datasets, we were able to model the three-dimensional organisation of the translocated chromosome in a PAX3:FOXO1 fusion-positive alveolar rhabdomyosarcoma cell line. We show that PAX3 and FOXO1 regulatory landscapes fuse into a novel TAD, allowing the PAX3 promoter to interact ectopically with FOXO1 sequences with potential enhancer function. The borders of this novel TAD correspond to the original 5'- and 3'- borders of the PAX3 and FOXO1 TADs, respectively, suggesting that TAD organisation precedes the formation of regulatory long-range interactions. Conclusions: Our results suggest that the chromosomal translocation that leads to ARMS development generates a novel TAD that favours ectopic PAX3:FOXO1 oncogene activation in non-PAX3 territories, which may be an essential step in the tumorigenic process, as expression in a particular cell type, the often elusive cell-of-origin, may be required for disease development.

2017-04-17 | GSE69439 | GEO

Identification of 17-DMAG as a novel KDM4B inhibitor for combination therapy [RNA-seq]

Project description:Histone lysine demethylases (KDMs) are emerging as therapeutic targets in cancer. Development of potent KDM inhibitors may provide additional options for epigenomics-oriented therapies. Using a Time-Resolved Fluorescence Resonance Energy Transfer (TR-FRET) functional demethylation assay, in combination with a high-content immunofluorescence imaging phenotypic screen, Matrix-Assisted Laser Desorption/Ionization- Fourier Transform Ion Cyclotron Resonance mass spectrometry (MALDI-FTICR MS) and Amplified Luminescent Proximity Homogeneous Assay (ALPHA), we identified geldanamycin, an inhibitor of heat shock protein 90 (Hsp90), as a novel inhibitor of JmjC-domain containing demethylases such as KDM4B. We further found that geldanamycin can destabilize the PAX3-FOXO1 fusion oncoprotein, an Hsp90 client, which is a driver of clinically unfavorable alveolar rhabdomyosarcoma (aRMS). We then hypothesized that dual inhibition of PAX3-FOXO1 and epigenetic modifiers of aRMS would have synergistic antitumor activity. We repurposed the geldanamycin analog 17-DMAG to target aRMS and found that 17-DMAG significantly delays tumor growth , extends survival in xenograft mouse models, and inhibits expression of PAX3-FOXO1 targets and multiple oncogenic pathways including MYC, E2F and NOTCH. In addition, the combination of 17-DMAG with conventional chemotherapy or the bromodomain inhibitor JQ1 significantly enhances therapeutic efficacy. In summary, we have identified geldanamycin and 17-DMAG as dual KDM/Hsp90 inhibitors and 17-DMAG is efficacious against PAX3-FOXO1-driven rhabdomyosarcoma.

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