Change in transcriptome upon G9a knockdown in RD ERMS (Embryonal Rhabdomyosarcoma) cells
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ABSTRACT:
PROVIDER: PRJNA598826 | ENA |
REPOSITORIES: ENA
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Project description:The Wnt signaling pathway is down-regulated in embryonal rhabdomyosarcoma (ERMS) and contributes to the block of myogenic differentiation. Epigenetic mechanisms leading to its suppression are unknown and could pave the way towards novel therapeutic modalities. In this study, we demonstrate that the lysine methyltransferase G9a suppresses the canonical Wnt signalling pathway by activating expression of the Wnt antagonist DKK1. Inhibition of G9a expression or activity reduced DKK1 expression and elevated canonical Wnt signalling resulting in myogenic differentiation in vitro and in vivo. Mechanistically, G9a impacted Sp1 and p300 enrichment at the DKK1 promoter in a methylation-dependent manner. The reduced tumor growth upon G9a deficiency was reversed by recombinant DKK1 or LGK974, which also inhibits Wnt signaling. Consistently, among thirteen drugs targeting chromatin modifiers, G9a inhibitors were highly effective in reducing ERMS cell viability. Together, our study demonstrates that ERMS cells are vulnerable to G9a inhibitors and suggest that targeting the G9a-DKK1--catenin node holds promise for differentiation therapy.
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Project description:We report here the analysis of TRPS1 chromatin binding by ChIP-Seq in embryonal rhabdomyosarcoma RD cells. We use here parental and TRPS1-KO RD cells. RD cells and RD-TRPS1-KO cells were cultured in growth medium and chromatin was prepared. TRPS1 DNA binding in RD cells and RD-TRPS1-KO cells using a selfmade antibody (referenced in Elster et al.) was determined by ChIP-seq.
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Project description:We report here the analysis of embryonal rhabdomyosarcoma RD cells by transcriptional profiling (bulk RNA-Seq). We use here inducible shRNAs to deplete TRPS1 in RD cells. RD cells were cultured in differentiation medium for 10 days and total RNA was extracted from control or shTRPS1 expressing cells and subjected to RNA-seq.
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Project description:A series of conditional mouse models of embryonal rhabdomyosarcoma, alveolar rhabdomyosarcoma and spindle cell sarcoma were generated and validated for relavence to corresponding human cancers. Conditional mouse models of embryonal rhabdomyosarcoma, alveolar rhabdomyosarcoma and spindle cell sarcoma were created by activation or deletion of Pax3:Fkhr, p53, Ptch1 or Rb1 genes.
2011-02-17 | E-GEOD-22520 | biostudies-arrayexpress
Project description:Embryonal rhabdomyosarcoma (ERMS) is the most common soft tissue cancer in children and is characterized by myogenic differentiation arrest. The prognosis of patients with relapsed or metastatic disease remains poor. ERMS genomes show few recurrent mutations, suggesting that other molecular mechanisms such as epigenetic regulation might play major role in driving ERMS tumor biology. In this study, we have demonstrated the diverse roles of HDACs in the pathogenesis of ERMS by characterizing effects of HDAC inhibitors, trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA; also known as vorinostat) in vitro and in vivo. TSA and SAHA suppress ERMS tumor growth and progression by inducing myogenic differentiation as well as reducing the self-renewal and migratory capacity of ERMS cells. To identify candidate genes that are differentially regulated in histone deacetylase inhibitor-treated embryonal rhabdomyosarcoma, a gene expression profiling study using the Affymetrix Human Gene 2.0 microarray platform and ingenuity pathway analysis of differentially expressed genes were performed on RD and 381T cells treated with trichostatin A or dimethyl sulfoxide (treatment vehicle).
2015-12-21 | E-GEOD-74970 | biostudies-arrayexpress
Project description:A series of conditional mouse models of embryonal rhabdomyosarcoma, alveolar rhabdomyosarcoma and spindle cell sarcoma were generated and validated for relavence to corresponding human cancers.
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Project description:The Hippo pathway effector YAP1 controls stem cell fate in epithelial tissues, but its role in stem cells of non-epithelial tissues, such as skeletal muscle, is poorly documented. Here we show that sustained YAP1 activity in mouse activated satellite cells in vivo induces rhabdomyosarcoma (RMS) resembling human embryonal RMS (ERMS) with high penetrance and short latency. The transcriptional program of YAP1 in ERMS drives pro-proliferative pathways whilst decreasing MyoD1 and MEF2 pro-differentiation activity to globally maintain the myoblastic phenotype of ERMS. Normalization of YAP1 expression reduced tumor burden and allowed myogenic differentiation of YAP1-driven and RD ERMS xenografts in situ, thereby identifying YAP1 as a potent RMS-causing oncogene and potential target for differentiation therapy. A total of four samples were analyzed. Two ChIP-Seq datasets from RD human cells, containing reads connected to TEAD binding and IgG binding as control/background; two ChIP-Seq datasets from YAP-ERMS mouse cells, containing reads connected to TEAD binding and Input reads as control/background
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Project description:Fluorescent-labeled zebrafish RAS-induced embryonal rhabdomyosarcoma (ERMS) were created to facilitate in vivo imaging of tumor-propagating cells, regional tumor heterogeneity, and dynamic cell movements in diverse cellular compartments. Using this strategy, we have identified a molecularly distinct ERMS cell subpopulation that expresses high levels of myf5 and is enriched for ERMS-propagating potential when compared with other tumor-derived cells. Embryonal rhabdomyosarcoma (ERMS) is an aggressive pediatric sarcoma of muscle. Here, we show that tumor-propagating potential is confined to myf5+ERMS cells and can be visualized in live, fluorescent transgenic zebrafish. During early tumor growth, myf5+ERMS cells reside within an expanded satellite cell compartment, but by late stage ERMS, myf5+cells are dynamically reorganized into distinct regions separated from differentiated tumor cells. Human ERMS also contain distinct areas of differentiated and undifferentiated cells. Time-lapse imaging revealed that myf5+ERMS cells populate newly formed tumor only after seeding by highly migratory myogenin+ ERMS cells. This finding helps explain the clinical observation that Myogenin positivity correlates with poor clinical outcome in human ERMS and suggests that differentiated tumor cells play critical roles in metastasis.
2012-12-01 | GSE32425 | GEO
Project description:Affymetrix SNP array data for embryonal rhabdomyosarcoma in a patient with Costello syndrome Affymetrix SNP array was performed according to the manufacturer's directions on DNA extracted from a fresh-frozen tumor sample.
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