Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Change in transcriptome upon G9a knockdown in RD ERMS (Embryonal Rhabdomyosarcoma) cells

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE142975 | GEO | 2020/12/16

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Transcription profiling of human cell lines reveals Dickkopf-1 is down-regulated by MYCN and inhibits neuroblastoma cell proliferation

Project description:Neuroblastomas are tumors of the developing peripheral sympathetic nervous system, which originates from the neural crest. Twenty percent of neuroblastomas show amplification of the MYCN oncogene, which correlates with poor prognosis. The MYCN transcription factor can activate and repress gene expression. To broaden our insight in the spectrum of genes down-regulated by MYCN, we generated gene expression profiles of the neuroblastoma cell lines SHEP-21N and SKNAS-NmycER, in which MYCN activity can be regulated. In this study, we show that MYCN suppresses the expression of Dickkopf-1 (DKK1) in both cell lines. DKK1 is a potent inhibitor of the wnt/ï?¢-catenin signalling cascade, which is known to function in neural crest cell migration. We generated a DKK1 inducible cell line, IMR32-DKK1, which showed impaired proliferation upon DKK1 expression. Surprisingly, DKK1 expression did not inhibit the canonical wnt/ï?¢-catenin signalling, suggesting a role of DKK1 in an alternative route of the wnt pathway. Gene expression profiling of two IMR32-DKK1 clones showed that only a few genes, amongst which SYNPO2, were up-regulated by DKK1. SYNPO2 encodes an actin-binding protein and was previously found to inhibit proliferation and invasiveness of prostate cancer cells. These results suggest that MYCN might stimulate cell proliferation by inhibiting the expression of DKK1. DKK1 might exert part of its growth suppressive effect by induction of SYNPO2 expression. Experiment Overall Design: Single time course experiment, including 4 time points

2008-06-16 | E-GEOD-8066 | biostudies-arrayexpress

Histone deacetylase inhibitors antagonize distinct pathways to suppress tumorigenesis of embryonal rhabdomyosarcoma.

2015-12-21 | GSE74970 | GEO

Dickkopf-1 is down-regulated by MYCN and inhibits neuroblastoma cell proliferation

Project description:Neuroblastomas are tumors of the developing peripheral sympathetic nervous system, which originates from the neural crest. Twenty percent of neuroblastomas show amplification of the MYCN oncogene, which correlates with poor prognosis. The MYCN transcription factor can activate and repress gene expression. To broaden our insight in the spectrum of genes down-regulated by MYCN, we generated gene expression profiles of the neuroblastoma cell lines SHEP-21N and SKNAS-NmycER, in which MYCN activity can be regulated. In this study, we show that MYCN suppresses the expression of Dickkopf-1 (DKK1) in both cell lines. DKK1 is a potent inhibitor of the wnt/beta-catenin signalling cascade, which is known to function in neural crest cell migration. We generated a DKK1 inducible cell line, IMR32-DKK1, which showed impaired proliferation upon DKK1 expression. Surprisingly, DKK1 expression did not inhibit the canonical wnt/beta-catenin signalling, suggesting a role of DKK1 in an alternative route of the wnt pathway. Gene expression profiling of two IMR32-DKK1 clones showed that only a few genes, amongst which SYNPO2, were up-regulated by DKK1. SYNPO2 encodes an actin-binding protein and was previously found to inhibit proliferation and invasiveness of prostate cancer cells. These results suggest that MYCN might stimulate cell proliferation by inhibiting the expression of DKK1. DKK1 might exert part of its growth suppressive effect by induction of SYNPO2 expression. Keywords: DKK1, MYCN, neuroblastoma, Dickkopf

2007-08-24 | GSE8066 | GEO

Histone deacetylase inhibitors antagonize distinct pathways to suppress tumorigenesis of embryonal rhabdomyosarcoma.

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

Expression data comparing human DKK1 and control vector transfected murine osteochondrosarcoma cells (MOS-J)

Project description:Canonical Wnt signaling controls proliferation and differentiation of osteogenic progenitor cells, and tumor-derived secretion of the Wnt antagonist Dickkopf-1 (Dkk1) is correlated with osteolyses and metastasis in many bone malignancies. However, the role of Dkk1 in the oncogenesis of primary osteosarcoma (OS) remains unexplored. Here, we over-expressed Dkk1 in the OS cell line MOS-J. Contrary to expectations, Dkk1 had autocrine effects on MOSJ cells in that it increased proliferation and resistance to metabolic stress in vitro. In vivo, Dkk1 expressing MOS-J cells formed larger and more destructive tumors than controls. These effects were attributed in part to up-regulation of the stress response enzyme and cancer stem cell marker aldehyde-dehydrogenase-1 (ALDH1) through Jun-N-terminal kinase signaling. This is the first report linking Dkk1 to tumor stress resistance, further supporting the targeting of Dkk1 not only to prevent and treat osteolytic bone lesions but also to reduce numbers of stress-resistant tumor cells. Two samples were analyzed, one human DKK1 transfected MOS-J cell sample and one control vector transfected MOS-J cell sample.

2012-12-22 | E-GEOD-43112 | biostudies-arrayexpress

Expression profiling of Wnt3a-treated HeLa cells in G1 and G2/M phase

Project description:The early transcriptional response of HeLa cervical carcinoma cells to the canonical Wnt signalling pathway was investigated at two different cell cycle phases (G1 and G2/M) via microarray gene expression profiling. HeLa cells grown under standard conditions were treated for 3 h with either Control, Wnt3a- or Dkk1-conditioned media and then FACS-sorted into G1 and G2/M populations for microarray expression analysis with 4 independent replicates per group.

2014-05-15 | E-GEOD-50248 | biostudies-arrayexpress

Gain-of-function genetic alterations of G9a drive oncogenesis II

Project description:Epigenetic regulators, when genomically altered, may become driver oncogenes that mediate otherwise unexplained pro-oncogenic changes lacking a clear genetic stimulus, such as activation of the WNT/b-catenin pathway in melanoma. This study identifies previously unrecognized recurrent activating mutations in the G9a histone methyltransferase gene, as well as G9a genomic copy gains in ~26% of human melanomas, which collectively drive tumor growth and an immunologically sterile microenvironment beyond melanoma. Furthermore, the WNT pathway is identified as a key tumorigenic target of G9a gain-of-function, via suppression of the WNT antagonist DKK1. Importantly, genetic or pharmacologic suppression of mutated or amplified G9a using multiple in vitro and in vivo models demonstrate that G9a is a druggable target for therapeutic intervention in melanoma and other cancers harboring G9a genomic aberrations.

2020-04-20 | GSE147427 | GEO

Gain-of-function genetic alterations of G9a drive oncogenesis I

2020-04-20 | GSE147419 | GEO