ArticleOncogene2018
EZH2 regulates neuroblastoma cell differentiation via NTRK1 promoter epigenetic modifications.
Article in Oncogene, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers.
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Who cites it
47 citing papers in PubMed, 79 citations in OpenAlex.
- Epigenetic Regulation of Trk Receptors and Neurotrophic Signalling in Neuroblastoma: Mechanisms, Plasticity, and Therapeutic Opportunities.International journal of molecular sciences · 2026Review
- Synthetic lethality of EZH2 and DNMT Inhibition suppresses neuroblastoma proliferation via MYCN destabilization.BMC cancer · 2025Article
- Targeting RBM10-Repressed RORB Activity in Liquid Condensates Inhibits Lysosomal Biogenesis and Neuroblastoma Progression via Affecting NF-κB Signaling.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Noncanonical PRC1.1 targets BTG2 to retain cyclin gene expression and cell growth in neuroblastoma.Oncogenesis · 2025Article
- Article
- Regulatory roles of insulin growth factor binding protein family in neuroblastoma cell proliferation and differentiation: Potential prognostic biomarkers and therapeutic targets for neuroblastoma.Pediatric discovery · 2024Review
- The transcriptional co-repressor Runx1t1 is essential for MYCN-driven neuroblastoma tumorigenesis.Nature communications · 2024Article
- Effects of transcription factorAnnals of surgical treatment and research · 2024Article
- NTRK1 knockdown induces mouse cognitive impairment and hippocampal neuronal damage through mitophagy suppression via inactivating the AMPK/ULK1/FUNDC1 pathway.Cell death discovery · 2023Article
- USP7 Inhibition Suppresses Neuroblastoma Growth via Induction of p53-Mediated Apoptosis and EZH2 and N-Myc Downregulation.International journal of molecular sciences · 2023Article
- Memory of stochastic single-cell apoptotic signaling promotes chemoresistance in neuroblastoma.Science advances · 2023Article
- Review
- Characterization and therapeutic perspectives of differentiation-inducing therapy in malignant tumors.Frontiers in genetics · 2023Review
- Article
- Polycomb EZH1 regulates cell cycle/5-fluorouracil sensitivity of neuroblastoma cells in concert with MYCN.Cancer science · 2022Article
- NanoacetylatedACS medicinal chemistry letters · 2022Article
- Downregulation of MEG3 and upregulation of EZH2 cooperatively promote neuroblastoma progression.Journal of cellular and molecular medicine · 2022Article
- KDM6B promotes activation of the oncogenic CDK4/6-pRB-E2F pathway by maintaining enhancer activity in MYCN-amplified neuroblastoma.Nature communications · 2021Article
- Combination of a synthetic retinoid and a DNA demethylating agent induced differentiation of neuroblastoma through retinoic acid signal reprogramming.British journal of cancer · 2021Article
- Targeting Oncogenic Transcriptional Networks in Neuroblastoma: From N-Myc to Epigenetic Drugs.International journal of molecular sciences · 2021Review
Corrections and comments
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Authors and funding
16 authors at 7 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The polycomb repressor complex 2 molecule EZH2 is now known to play a role in essential cellular processes, namely, cell fate decisions, cell cycle regulation, senescence, cell differentiation, and cancer development/progression. EZH2 inhibitors have recently been developed; however, their effectiveness and underlying molecular mechanisms in many malignancies have not yet been elucidated in detail. Although the functional role of EZH2 in tumorigenesis in neuroblastoma (NB) has been investigated, mutations of EZH2 have not been reported. A Kaplan-Meier analysis on the event free survival and overall survival of NB patients indicated that the high expression of EZH2 correlated with an unfavorable prognosis. In order to elucidate the functional roles of EZH2 in NB tumorigenesis and its aggressiveness, we knocked down EZH2 in NB cell lines using lentivirus systems. The knockdown of EZH2 significantly induced NB cell differentiation, e.g., neurite extension, and the neuronal differentiation markers, NF68 and GAP43. EZH2 inhibitors also induced NB cell differentiation. We performed a comprehensive transcriptome analysis using Human Gene Expression Microarrays and found that NTRK1 (TrkA) is one of the EZH2-related suppression targets. The depletion of NTRK1 canceled EZH2 knockdown-induced NB cell differentiation. Our integrative methylome, transcriptome, and chromatin immunoprecipitation assays using NB cell lines and clinical samples clarified that the NTRK1 P1 and P2 promoter regions were regulated differently by DNA methylation and EZH2-related histone modifications. The NTRK1 transcript variants 1/2, which were regulated by EZH2-related H3K27me3 modifications at the P1 promoter region, were strongly expressed in favorable, but not unfavorable NB. The depletion and inhibition of EZH2 successfully induced NTRK1 transcripts and functional proteins. Collectively, these results indicate that EZH2 plays important roles in preventing the differentiation of NB cells and also that EZH2-related NTRK1 transcriptional regulation may be the key pathway for NB cell differentiation.
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