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Polycomb EZH1 regulates cell cycle/5-fluorouracil sensitivity of neuroblastoma cells in concert with MYCN

Yoshitaka Shinno1,2, Hisanori Takenobu1, Ryuichi P Sugino1

  • 1Research Institute for Clinical Oncology, Saitama Cancer Center, Saitama, Japan.

Cancer Science
|September 2, 2022
PubMed

Insights

Depleting enhancer of zeste homolog 1 (EZH1) in neuroblastoma cells caused cell death and inhibited tumor growth. EZH1 inhibition also sensitized cells to 5-fluorouracil, suggesting a new epigenetic treatment strategy.

Area of Science:

  • Oncology
  • Epigenetics
  • Molecular Biology

Background:

  • MYCN-amplified neuroblastoma is an aggressive pediatric cancer.
  • Neuroblastoma cells often exhibit resistance to conventional chemotherapies like 5-fluorouracil (5-FU).
  • EZH1 plays a role in epigenetic regulation and has been implicated in various cancers.

Purpose of the Study:

  • To investigate the role of EZH1 in MYCN-amplified neuroblastoma.
  • To explore the potential of EZH1 inhibition as a therapeutic strategy for neuroblastoma.
  • To determine if EZH1 inhibition can overcome resistance to 5-FU.

Main Methods:

  • Depletion of EZH1 in MYCN-amplified neuroblastoma cell lines.
  • Analysis of cell death and xenograft tumor growth.
  • Measurement of H3K27me1 levels and MYCN/EZH1 protein interactions.
  • Transcriptome analysis and Gene Set Enrichment Analysis (GSEA).
  • Treatment with the EZH1/2 inhibitor UNC1999 and assessment of its effects on cell viability, H3K27 methylation, TYMS levels, and sensitization to 5-FU.

Main Results:

  • EZH1 depletion led to significant neuroblastoma cell death and xenograft inhibition.
  • EZH1 depletion decreased H3K27me1 levels and affected the MYCN/EZH1 interaction, impacting epigenetic regulation.
  • Transcriptome analysis revealed downregulation of cell cycle progression, including E2F-mediated DNA replication pathways and key genes like TYMS, POLA2, and CCNA1.
  • The EZH1/2 inhibitor UNC1999 induced cell death, reduced H3K27 methylation, and decreased TYMS levels.
  • UNC1999 treatment sensitized MYCN-amplified neuroblastoma cells to 5-FU, overcoming drug resistance.

Conclusions:

  • EZH1 plays a critical role in the survival and proliferation of MYCN-amplified neuroblastoma cells.
  • EZH1 inhibition, through genetic depletion or pharmacological targeting, represents a promising therapeutic approach for neuroblastoma.
  • Combining EZH inhibition with 5-FU may be an effective strategy to treat 5-FU-resistant neuroblastoma.
Keywords:
5-FUEZH1MYCNTYMSneuroblastoma

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