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多梳抑制复合物 EZH1 与 MYCN 协同调节神经母细胞瘤细胞的细胞周期/5-氟尿嘧啶敏感性。

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

机构信息

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

Department of Pediatric Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.

出版信息

Cancer Sci. 2022 Dec;113(12):4193-4206. doi: 10.1111/cas.15555. Epub 2022 Oct 7.

DOI:10.1111/cas.15555
PMID:36052716
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9746046/
Abstract

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 downregulation of the cell cycle progression-related pathway. In particular, Gene Set Enrichment Analysis revealed downregulation 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 neuroblastoma 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 could be an effective strategy for development of a new epigenetic treatment for neuroblastoma.

摘要

在本研究中，我们发现 EZH1 在 MYCN 扩增神经母细胞瘤细胞中的缺失导致了显著的细胞死亡和异种移植物抑制。EZH1 的缺失降低了 H3K27me1 的水平；MYCN 和 EZH1 的相互作用和蛋白稳定似乎在表观遗传转录调控中发挥作用。EZH1 缺失细胞的转录组分析导致细胞周期进展相关途径的下调。特别是，基因集富集分析揭示了 E2F 介导的 DNA 复制的反应组下调以及该过程的关键基因，TYMS、POLA2 和 CCNA1。TYMS 和 POLA2 被 MYCN 和 EZH1 相关的表观遗传修饰转录激活。EZH1/2 抑制剂 UNC1999 的治疗也诱导了细胞死亡，降低了 H3K27 甲基化，并降低了神经母细胞瘤细胞中的 TYMS 水平。先前的报告表明神经母细胞瘤细胞对 5-氟尿嘧啶（5-FU）具有抗性，而 TYMS（编码胸苷酸合成酶）被认为是叶酸类似物的主要作用部位。有趣的是，UNC1999 治疗显著增加了 MYCN 扩增神经母细胞瘤细胞对 5-FU 治疗的敏感性，这表明 EZH 抑制可能是开发神经母细胞瘤新的表观遗传治疗方法的有效策略。

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