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Epigenetic biomarkers for EZH2 inhibitor sensitivity in neuroblastoma

ABSTRACT: Epigenetic biomarkers for EZH2 inhibitor sensitivity in neuroblastoma

PROVIDER: PRJNA680478 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR13125064.fastq.gz	Fastqsanger.gz
	SRR13125065.fastq.gz	Fastqsanger.gz
	SRR13125066.fastq.gz	Fastqsanger.gz
	SRR13125067.fastq.gz	Fastqsanger.gz
	SRR13125068.fastq.gz	Fastqsanger.gz

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Epigenetic biomarkers for EZH2 inhibitor sensitivity in neuroblastoma [array]

Project description:Epigenetic biomarkers for EZH2 inhibitor sensitivity in neuroblastoma [array]

| PRJNA680480 | ENA

Epigenetic biomarkers for EZH2 inhibitor sensitivity in neuroblastoma [ChIP-seq]

Project description:Epigenetic biomarkers for EZH2 inhibitor sensitivity in neuroblastoma [ChIP-seq]

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Epigenetic biomarkers for EZH2 inhibitor sensitivity in neuroblastoma [array]

Project description:EZH2 is a H3K27 methylase and a target of cancer epigenetic treatments. We recently reported the oncogenic roles and NTRK1 (TRKA) epigenetic regulation by EZH2 in the MYCN-amplified aggressive neuroblastomas (NB) (L. Here, we investigated the effects and function of small molecule EZH2 inhibitor (EZH2i) on aggressive NB model cell lines. We examined the antitumor effects of EZH2i using WST assay and colony formation assay. By EZH2i treatments, suppression of proliferation, G0/G1 cell cycle arrest, and apoptosis were observed in sensitive NB cells dose-dependently, whereas they were not observed in resistant NB cells. Transcriptome analysis and GSEA indicated significant changes were observed in the gene set related to differentiation and cell cycle arrest in the sensitive cells. We selected genes induced at mRNA level by EZH2i only in the sensitive cells and confirmed tumor suppressor function in NB cells. Almost of the EZH2i-induced gene promoters were marked by H3K27me3 in the sensitive NB cell line. Interestingly, a part of the EZH2i-induced gene promoters have CpG islands and methylated in NB tumor samples registered in databases and the EZH2i-resistant NB cells. Further, combination of EPZ-6438 and 5-aza-deoxycitide, resulted in effective suppression of proliferation in the EPZ-6438-resistant 3 NB cell lines. Transcriptome/methylome analysis of the EPZ-6438 and 5-aza-deoxycitide-treated NB cells revealed the combinational epigenetic regulation of the tumor suppressors and oncogene expression. Finally, we found that methylome analysis of the promoter regions, e.g. VSTM2L, GPNMB, and TIMP3 CpG islands can be biomarkers of EPZ-6438-registancy in unfavorable NB patients. These responsible CpG island methylation appears to be biomarkers for the application of EZH2i/DNMTi combination therapy.

2020-11-25 | GSE162058 | GEO

Epigenetic biomarkers for EZH2 inhibitor sensitivity in neuroblastoma [ChIP-seq]

2020-11-25 | GSE162057 | GEO

Genome methylation defines EZH2 inhibitor resistance in neuroblastoma

Project description:Genome methylation defines EZH2 inhibitor resistance in neuroblastoma

| PRJNA601429 | ENA

Genome methylation defines EZH2 inhibitor resistance in neuroblastoma [II]

Project description:Genome methylation defines EZH2 inhibitor resistance in neuroblastoma [II]

| PRJNA601432 | ENA

Genome methylation defines EZH2 inhibitor resistance in neuroblastoma [I]

Project description:Genome methylation defines EZH2 inhibitor resistance in neuroblastoma [I]

| PRJNA601431 | ENA

Dysregulated lipid metabolism blunts the sensitivity of B16F10 melanoma cells to EZH2 inhibitor

Project description:The sensitivity has been the key issue for EZH2 inhibitor in cancer therapy. Although it has been approved by Food and Drug Administration (FDA) in 2020, the relative narrow scope still limits its clinical application. In this study, we utilized B16F10 melanoma cell line which is resistant to EZH2 inhibitor GSK126 to an extent to investigate the underlying mechanism. We found that although the proliferative phenotype didn't show any difference upon treatment with GSK126 at 10 μM, the transcriptome and metabolome changed profoundly. Gene set enrichment analysis and metabolites pathway enrichment analysis revealed that GSK126 induced broad shifts in glucose, amino acids and lipid metabolism. Lipid synthesis were strengthened with elevated abundance of unsaturated fatty acids. We also found attenuated tricarboxylic acid cycle metabolism, and decreased amino acids levels. The liver lipid accumulation and the increased blood triglycerides level after GSK126 treatment were further confirmed in a mouse model. Indeed, the combination of GSK126 and lipolysis agent fenofibrate significantly attenuated the proliferation of B16F10 and increased the sensitivity to GSK126. Therefore, the dysregulated lipid metabolism blunts the sensitivity of B16F10 to GSK126. This study uncovered the iceberg under the sea and identified the Achilles heel of EZH2 inhibitor, so that it provides the novel strategy for further combination therapy.

2022-02-23 | GSE163078 | GEO

Epigenetic biomarkers for EZH2 inhibitor sensitivity in neuroblastoma

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-11-25 | GSE162059 | GEO

Targeting EZH2 in MYCN-amplified Neuroblastoma [ChIP-seq]

Project description:Purpose: Identify new targets in MYCN-amplified Neuroblastoma Methods: ChIP-Seq experiments were performed on Kelly and LAN-1 neuroblastoma cells by using the following antibodies: anti-EZH2 (Cell Signaling 5246S); anti-H3K27me3 (Millipore 07-449); anti-H3K4me3 (Abcam ab8580). We evaluated the global EZH2 PRC2-dependence by identifiying direct genome-wide target genes for EZH2, H3K27me3 and H3K4me3. Results: We found that EZH2 serves a PRC2-dependent function in neuroblastoma, repressing neuronal differentiation. Moreover, EZH2-regulated genes were strongly repressed in MYCN-amplified and high-risk primary tumors. Conclusion: Our study supports testing EZH2 inhibitors in patients with MYCN-amplified neuroblastoma.

2017-12-02 | GSE85430 | GEO

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