PRC2 molecule EED is a target of epigenetic therapy of neuroblastoma
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE183369 | GEO | 2022/09/03
REPOSITORIES: GEO
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Project description:Polo-Like Kinase 1 (PLK1), a serine/threonine kinase involved in cell cycle regulation at the G2/M transition, is associated with high-risk neuroblastoma (NB) and unfavorable patient outcome. Recently, we and others demonstrated that PLK1 is a potential drug target in neuroblastoma and reported antitumoral actvity of the PLK1 inhibitor BI2536 in preclinical models of NB. We here analyzed the effects of the ATP-competitive PLK1 inhibitor GSK461364 on typical tumorigenic properties of preclinical in vitro and in vivo models of NB. Treatment of NB cells with GSK461364 resulted in decreased cell viability and reduction of proliferative capacity, and led to cell cycle arrest and massive induction of apoptosis. These phenotypic consequences were observed at low-dose nanomolar levels and were independent of the MYCN copy number status of the cell lines. In vivo treatment with GSK461364 led to a strong delay in tumor development and to a highly significant increase in survival in the treatment group. These preclinical findings highlight the promise of PLK1 inhibitors as novel agents for NB and serve as rationale to move forward with early phase clinical trials in children.
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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.
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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.
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Project description:In the present study, we found that EZH1 depletion in MYCN-amplified neuroblastoma cells resulted in significant cell death as well as xenograft inhibition. EZH1 depletion decreased the level of H3K27me1; the interaction and protein stabilization of MYCN and EZH1 appear to play roles in epigenetic transcriptional regulation. Transcriptome analysis of EZH1-depleted cells resulted in down-regulation of the cell cycle progression-related pathway. In particular, GSEA revealed down-regulation of reactome E2F-mediated regulation of DNA replication along with key genes of this process, TYMS, POLA2, and CCNA1. TYMS and POLA2 were transcriptionally activated by MYCN and EZH1-related epigenetic modification. Treatment with the EZH1/2 inhibitor UNC1999 also induced cell death, decreased H3K27 methylation, and reduced the levels of TYMS in NB cells. Previous reports indicated neuroblastoma cells are resistant to 5-fluorouracil (5-FU) and TYMS (encoding thymidylate synthetase) has been considered the primary site of action for folate analogues. Intriguingly, UNC1999 treatment significantly sensitized MYCN-amplified neuroblastoma cells to 5-FU treatment, suggesting that EZH inhibition may be an effective strategy for development of a new epigenetic treatment for neuroblastoma.
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