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对m5C修饰调节者的景观分析揭示了肝细胞癌中DNMT1介导的皮里米丁代谢失调

Xuhui Zhao^1,2,3, Shengwei Mao^1,2, Yuan Fang^1,2

¹Department of Hepatobiliary Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Research Unit of Liver Cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Beijing, People's Republic of China.

Clinical epigenetics

|August 23, 2025

概括

增加的5-甲基细胞素 (m5C) 修饰通过上调循环素依赖激酶1 (CDK1) 和胺代谢来促进肝细胞癌 (HCC) 的进展. 针对这个DNMT1/CDK1轴为HCC提供了一个有希望的治疗策略.

科学领域:

癌症学
分子生物学
生物化学

背景情况:

5甲基细胞素 (m5C) 是一种关键的RNA修饰,涉及各种癌症.
在肝细胞癌 (HCC) 中m5C的确切作用和机制在很大程度上仍未明确.

研究的目的:

研究m5C修饰在HCC发育和进展中的作用.
确定参与m5C介导的HCC代谢失调的关键分子参与者和途径.
评估针对HCC中确定的m5C相关轴的治疗潜力.

主要方法:

在HCC组织中分析m5C水平和与临床结果的相关性.
在HCC中对代谢特征进行景观分析.
研究DNA甲基转移酶1 (DNMT1),循环素依赖激酶1 (CDK1) 和胺代谢之间的调节关系.
在HCC细胞中除DNMT1或CDK1的体外研究.
使用向抑制剂治疗的HCC模型小鼠的体内研究.

主要成果:

在HCC中异常升高的m5C水平与瘤进展和不良预后相关.
通过DNMT1及其下游效应体CDK1调节的胺代谢被确定.
DNMT1以依赖m5C的方式对CDK1进行上调,促进皮里米丁代谢.
抑制了DNMT1或CDK1的HCC细胞增殖,入侵和迁移.
在体内有效抑制DNMT1/CDK1/pyrimidine代谢轴的药理向.

结论:

通过DNMT1介导的m5C修饰稳定了CDK1mRNA,增强了对HCC进展至关重要的pyrimidine代谢.
DNMT1/CDK1/pyrimidine代谢轴是HCC的一个重要驱动因素.
针对这一轴为肝细胞癌提供了可行的治疗策略.

关键词:

循环素依赖蛋白激酶1 DNA-甲基转移酶1 美国胺的代谢 m5C 修改

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