Genome methylation defines EZH2 inhibitor resistance in neuroblastoma [II]
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PROVIDER: PRJNA601432 | ENA |
REPOSITORIES: ENA
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Project description:Genome methylation defines EZH2 inhibitor resistance in neuroblastoma
| PRJNA601429 | ENA
Project description:Genome methylation defines EZH2 inhibitor resistance in neuroblastoma [I]
| PRJNA601431 | ENA
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) (Li et al., ONCOGENE, 2018). 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 was observed in SK-N-SH and SK-N-BE cells (sensitive cells) dose-dependently, whereas it was not observed in IMR32 and NGP cells (resistant cells). FACS analysis showed apoptosis and G0/G1 cell cycle arrest in sensitive cells. Transcriptome analysis and GSEA indicated significant changes were observed in the gene set related to cell cycle arrest and differentiation 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 MYCN-amplified NB cell lines. Interestingly, a part of the EZH2i-induced gene promoters have CpG islands and methylated in NB tumor samples registrated in databases. Further, combination of EPZ6438 and 5-aza-deoxycitide, resulted in effective suppression of proliferation in the EPZ6438-resistant 3 NB cell lines. Transcriptome/methylome analysis of the EPZ6438 and 5-aza-deoxycitide-treated NB cells revealed the combinational epigenetic regulation of the tumor suppressors and oncogene expression. Finally, methylome analysis of the promoter regions, e.g. VSTM2L, GPNMB, and TIMP3 CpG islands can be biomarkers of EPZ6438-registancy in unfavorable NB patients. These responsible CpG island methylation as biomarkers for the application of EZH2i/DNMTi combination therapy.
2022-08-01 | GSE143712 | GEO
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) (Li et al., ONCOGENE, 2018). 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 was observed in SK-N-SH and SK-N-BE cells (sensitive cells) dose-dependently, whereas it was not observed in IMR32 and NGP cells (resistant cells). FACS analysis showed apoptosis and G0/G1 cell cycle arrest in sensitive cells. Transcriptome analysis and GSEA indicated significant changes were observed in the gene set related to cell cycle arrest and differentiation 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 MYCN-amplified NB cell lines. Interestingly, a part of the EZH2i-induced gene promoters have CpG islands and methylated in NB tumor samples registrated in databases. Further, combination of EPZ6438 and 5-aza-deoxycitide, resulted in effective suppression of proliferation in the EPZ6438-resistant 3 NB cell lines. Transcriptome/methylome analysis of the EPZ6438 and 5-aza-deoxycitide-treated NB cells revealed the combinational epigenetic regulation of the tumor suppressors and oncogene expression. Finally, methylome analysis of the promoter regions, e.g. VSTM2L, GPNMB, and TIMP3 CpG islands can be biomarkers of EPZ6438-registancy in unfavorable NB patients. These responsible CpG island methylation as biomarkers for the application of EZH2i/DNMTi combination therapy.
2022-08-01 | GSE143713 | GEO
Project description:Epigenetic biomarkers for EZH2 inhibitor sensitivity in neuroblastoma
| PRJNA680478 | ENA
Project description:Epigenetic biomarkers for EZH2 inhibitor sensitivity in neuroblastoma [array]
| PRJNA680480 | ENA
Project description:Epigenetic biomarkers for EZH2 inhibitor sensitivity in neuroblastoma [ChIP-seq]
| PRJNA680475 | ENA
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
Project description:Efforts to therapeutically target EZH2 have generally focused on inhibition of its methyltransferase activity, although it remains less clear whether this is the central mechanism whereby EZH2 promotes cancer. We demonstrate that EZH2 directly interacts with both MYC family oncoproteins, MYC and MYCN, and promotes their stabilization in a methyltransferase-independent manner. By competing against the SCFFBW7 ubiquitin ligase to bind MYC and MYCN, EZH2 counteracted FBW7-mediated MYC(N) polyubiquitination and proteasomal degradation. Depletion, but not enzymatic inhibition, of EZH2 induced robust MYC(N) degradation and inhibited tumor cell growth in MYC(N) driven neuroblastoma and small cell lung cancer. These findings unveil the MYC family proteins as global EZH2 oncogenic effectors and EZH2 pharmacologic degraders as potential MYC(N) targeted cancer therapeutics, pointing out that MYC(N) driven cancers may develop inherent resistance to the canonical EZH2 enzymatic inhibitors currently in clinical development.
2022-02-17 | PXD029652 | Pride
Project description:Purpose: Identify new targets in MYCN-amplified Neuroblastoma Methods: Kelly and LAN-1 neuroblastoma cells were treated in duplicate with 2 uM GSK126 (Excess Biosciences M60071-2) or DMSO for 2 or 5 days. RNA was extracted from cells with the RNeasy Kit (Qiagen). RNA libraries were prepared for sequencing using standard Illumina protocols. The pool of sixteen samples was sequenced on two lanes of an Illumina HiSeq, generating single end reads of 32-76 bp length. Transcript abundance (reads and FPKM scores) at GRCh37/hg19 RefSeq gene level was computed with the Feature Counts method implemented in the Bioconductor v3.2 Rsubread package (Liao et al., 2014). Results: Pharmacological suppression of EZH2 inhibited neuroblastoma growth. Transcriptomic analysis revealed that EZH2 serves a PRC2-dependent function in neuroblastoma, repressing neural differentiation. Moreover, EZH2-regulated genes were strongly repressed in MYCN-amplified and high risk primary tumors. These observations demonstrate that MYCN upregulates EZH2 leading to inactivation of a tumor suppressor program in neuroblastoma. Conclusion: Our study supports testing EZH2 inhibitors in patients with MYCN-amplified neuroblastoma.
2017-12-02 | GSE85431 | GEO