Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

EZH2-mediated primary cilium deconstruction drives metastatic melanoma formation

ABSTRACT: Human melanomas frequently harbor amplifications of EZH2. However, the oncogenic contribution of this methyltransferase to melanoma formation has remained elusive. Taking advantage of murine melanoma models, we now show that EZH2 drives tumorigenesis from benign BrafV600E or NrasQ61K-expressing melanocytes. EZH2 oncogenicity results from silencing of genes relevant for the integrity of the primary cilium, a signaling organelle projecting from the surface of vertebrate cells. Consequently, gain of EZH2 function promotes loss of primary cilia in benign melanocytic lesions. In contrast, blockade of EZH2 activity evokes ciliogenesis and cilia-dependent growth inhibition in malignant melanoma. Finally, we demonstrate that loss of cilia enhances pro-tumorigenic WNT/β-catenin signaling and is itself sufficient to drive metastatic melanoma in benign cells. Thus, primary cilia deconstruction is a key process in EZH2-driven melanomagenesis.

ORGANISM(S): Mus musculus

PROVIDER: GSE112677 | GEO | 2019/04/04

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

EZH2-mediated primary cilium deconstruction drives metastatic melanoma formation

Project description:EZH2-mediated primary cilium deconstruction drives metastatic melanoma formation

| PRJNA448706 | ENA

050209-miRNA Melanoma miRNA microarray

Project description:To identify improved molecular markers to support histological examination we used microarray analysis of formalin-fixed and paraffin-embedded samples from different stages of melanomagenesis to identify differentially expressed microRNAs. Total RNA were obtained from isolated 19 human cell lines and 52 FFPE human samples. Cells include 2 immortalised melanocytes, 4 ovarian cancer cell lines and 13 melanoma cell lines. 61 FFPE samples include 11 benign naevi, 20 primary and 21 metastatic melanoma

2012-02-08 | E-GEOD-35579 | biostudies-arrayexpress

The epigenetic modifier EZH2 controls melanoma growth and metastasis through silencing of distinct tumour suppressors

Project description:Increased activity of the epigenetic modifier EZH2 has been associated with different cancers. However, evidence for a functional role of EZH2 in tumourigenesis in vivo remains poor, in particular in metastasising solid cancers. Here we reveal central roles of EZH2 in promoting growth and metastasis of cutaneous melanoma. In a melanoma mouse model, conditional Ezh2 ablation as much as treatment with the preclinical Ezh2 inhibitor GSK503 stabilises the disease through inhibition of growth and virtually abolishes metastases formation without affecting normal melanocyte biology. Comparably, in human melanoma cells, EZH2 inactivation impairs proliferation and invasiveness, accompanied by re-expression of tumour suppressors connected to increased patient survival. These EZH2 target genes suppress melanoma growth and prevent EMT / metastasis in vivo revealing the dual function of EZH2 in promoting tumour progression. Thus, EZH2-mediated epigenetic repression is highly relevant especially during advanced melanomagenesis, which makes EZH2 a promising target for novel melanoma therapies.

2014-11-12 | GSE63165 | GEO

Gene expression profiling of isogenic malignant melanoma A375-BRAFV600E/NRASQ61 and A375-BRAFV600E/NRASQ61K cell lines

Project description:BRAF-inhibitor (BRAFi)-resistance compromises long term survivorship of malignant melanoma patients, and mutant NRAS is a major mediator of BRAFi-resistance. We have employed NanoString nCounterTM transcriptomic analysis of isogenic human malignant melanoma cells that differ only by NRAS mutational status (BRAFi-sensitive A375-BRAFV600E/NRASQ61 versus BRAFi-resistant A375-BRAFV600E/NRASQ61K), identifying modulation of specific gene expression networks as a function of NRASQ61K-status.

2021-09-23 | GSE184633 | GEO

Tumor suppressor role of Ezh2 in an NRASQ61K driven model of Early T-cell Precursor Acute Lymphoblastic Leukemia (ChIP-Seq)

Project description:Purpose: To characterize changes in genome-wide H3K27me3 associated with homozygous inactivation the Polycomb Repressive Complex 2 (PRC2) lysine methyltransferase Ezh2 in a mouse model of earlt T-cell precursor ALL (ETP-ALL) Methods: We performed Chip-seq for the H3K27me3 Chromatin mark on Ezh2ff and Ezh2ko cells NRASQ61K leukemias. Results: Inactivation of Ezh2 in this model leads to accelerated leukemia development. Resulting gene expression changes are complex and include enrichment of genes associated with immature hematopoietic cells, Ras signaling and Cytokines and their cognate receptors. Genes that lose K27me3 in Ezh2ko vs. Ezh2ff cells (ChIP-Seq) are enriched by GSEA in Ezh2ko vs Ezh2ff cells. Conclusions: Inactivation of Ezh2 in our model leads to accentuated expression of early hematopoietic gene expression programs, to accentuated growth and survival signaling and to transcriptonal enrichment of PRC2 targets. ChIP-Seq for H3K27me3 using Ezh2ff and Ezh2ko NRASQ61K leukemias harvested from leukemic mice and expanded on OP9DL1 cells.

2016-01-07 | E-GEOD-76601 | biostudies-arrayexpress

Transcriptional targets of oncogenic RAS proteins that mediate their ability to induce cellular transformation

Project description:Mutations in the NRAS oncogene are present in up to 20% of melanoma. Here, we show that interferon alpha-inducible protein 6 (IFI6) is necessary for NRASQ61K-induced transformation and melanoma growth. IFI6 was transcriptionally upregulated by NRASQ61K, and knockdown of IFI6 resulted in DNA replication stress due to dysregulated DNA replication via E2F2. This stress consequentially inhibited cellular transformation and melanoma growth via senescence or apoptosis induction depending on the RB and p53 pathway status of the cells. NRAS-mutant melanoma were significantly more resistant to the cytotoxic effects of DNA replication stress-inducing drugs, and knockdown of IFI6 increased sensitivity to these drugs. Pharmacological inhibition of IFI6 expression by the MEK inhibitor trametinib, when combined with DNA replication stress-inducing drugs, blocked NRAS-mutant melanoma growth. Collectively, we demonstrate that IFI6, via E2F2 regulates DNA replication and melanoma development and growth, and this pathway can be pharmacologically targeted to inhibit NRAS-mutant melanoma. MEL-ST cells expressing either empty vector or mutant oncogenic RAS genes (HRAS v12, KRAS v12, NRAS Q61K) were used to isolate total RNA. The RNA was then used to perform gene expression analyses using the Illumina HumanHT-12 V4.0 Expression BeadChip array.

2016-09-08 | E-GEOD-62827 | biostudies-arrayexpress

Regulators of NRAS-mediated transformation and melanoma tumor maintenance

Project description:Mutations in the NRAS oncogene are present in up to 20% of melanoma. Here, we show that interferon alpha-inducible protein 6 (IFI6) is necessary for NRASQ61K-induced transformation and melanoma growth. IFI6 was transcriptionally upregulated by NRASQ61K, and knockdown of IFI6 resulted in DNA replication stress due to dysregulated DNA replication via E2F2. This stress consequentially inhibited cellular transformation and melanoma growth via senescence or apoptosis induction depending on the RB and p53 pathway status of the cells. NRAS-mutant melanoma were significantly more resistant to the cytotoxic effects of DNA replication stress-inducing drugs, and knockdown of IFI6 increased sensitivity to these drugs. Pharmacological inhibition of IFI6 expression by the MEK inhibitor trametinib, when combined with DNA replication stress-inducing drugs, blocked NRAS-mutant melanoma growth. Collectively, we demonstrate that IFI6, via E2F2 regulates DNA replication and melanoma development and growth, and this pathway can be pharmacologically targeted to inhibit NRAS-mutant melanoma. YUGASP cells stably expressing a non-silencing shRNA or two individual shRNAs against IFI6 were used to prepare the total RNA, which was then used to analyze for gene expression using Illumina expression array.

2016-09-08 | E-GEOD-69933 | biostudies-arrayexpress

Transcriptional targets of oncogenic RAS proteins that mediate their ability to induce cellular transformation

2016-09-08 | GSE62827 | GEO

Regulators of NRAS-mediated transformation and melanoma tumor maintenance

2016-09-08 | GSE69933 | GEO

The influence of melanoma extracellular vesicles on benign melanocytes, dermal fibroblasts and microvascular endothelial cells.

Project description:This study investigates the role of PRAME (Preferentially Expressed Antigen in Melanoma), a cancer-testis antigen, in melanoma progression, particularly its function in melanoma-derived extracellular vesicles (EVs) and its impact on benign primary melanocytes (PM), primary fibroblasts(PF) and microvascular endothelial cells (EN).

2024-10-16 | GSE279329 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data