MDM2对手Nutlin-3通过增强p53-TET1信号轴来刺激全球DNA的基甲基化
Danni Wu1,2,3, Yao Li1, Cuiping Li1
1State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China.
ACS chemical biology
|July 18, 2023
概括
抗癌药物努特林-3通过激活p53-TET1相互作用,促进TP53野生类型癌细胞中的DNA基甲基化. 这一过程增强了p53的激活,通过积极的反循环促进了细胞亡.
科学领域:
- 表观遗传学和癌症生物学
- 分子瘤学分子瘤学
- 基因组的修改 基因组的修改
背景情况:
- 由5-基甲基细胞素 (5hmC) 标记的DNA基甲基化对于细胞过程如发育和瘤抑制至关重要.
- 酶的TET家族 (TET1,TET2,TET3) 催化了5-甲基细胞素 (5mC) 转化为5hmC的过程.
研究的目的:
- 为了研究抗癌剂nutlin-3对DNA基甲基化作用.
- 阐明TP53和TET蛋白在nutlin-3介导的表观遗传变化中的作用.
主要方法:
- 在用nutlin-3治疗的癌细胞中评估全球DNA基甲基化水平 (5hmC).
- 分析TET1,TET2和TET3蛋白的表达.
- 使用免疫沉研究p53和TET1之间的相互作用.
- 评估TET1敲击对nutlin-3影响的影响.
主要成果:
- 努特林-3在TP53野生型癌细胞中选择性地增加了全球DNA基甲基化,但在TP53突变细胞中没有.
- 努特林-3激活了野生型TP53,但没有突变TP53,这与其作为MDM2抗剂的作用相一致.
- TET1倒置抑制了nutlin-3诱导的DNA基甲基化和TP53/P21激活.
- 发现p53与TET1.1强烈相互作用.
结论:
- 努特林-3以TP53依赖的方式刺激DNA基甲基化和亡.
- 一个涉及p53-TET1相互作用的积极反循环增强了p53的激活,并促进了亡.
- 努特林-3代表了针对癌症表观遗传修饰的潜在治疗策略.
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