抑制BRD4抑制了基因组H4的UFMylation,通过TXNIP增加了ferroptosis的敏感性
Zhen Yang1, Baoshuai Wang1, Bin Guo1
1State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, People's Republic of China.
Cell death & disease
|November 17, 2025
概括
BET 抑制剂 JQ1 调节TXNIP,通过抑制组素修饰和促进细胞休眠来调节抗瘤效应. 休眠细胞对铁亡很敏感,增强了组合治疗的潜力.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 表观遗传学 在表观遗传学中,表观遗传学是指表观遗传学.
背景情况:
- 基因和BET抑制剂,如JQ1,改变基因转录,但它们在固体瘤中的特定标尚不清楚.
- 了解这些目标对于优化BET抑制剂在癌症治疗中的疗效至关重要.
研究的目的:
- 在固体瘤中识别介导BET抑制剂JQ1抗瘤作用的基因.
- 阐明JQ1影响基因转录,蛋白质修饰和细胞命运的分子机制.
- 探索这些发现对组合疗法的影响.
主要方法:
- 用BET抑制剂JQ1.1.治疗固体癌细胞的方法
- 分析基因转录,基因组修饰 (H3K9三甲基化,H4UFMylation) 和蛋白质稳定性 (P27).
- 调查雷素相互作用蛋白 (TXNIP) 和UFMylation在细胞对JQ1.1反应中的作用.
主要成果:
- JQ1通过降低H4 UFMylation和抑制cMYC驱动的细胞周期进展来调节TXNIP,该TXNIP通过减少H4 UFMylation和抑制cMYC驱动的细胞周期进展来调节其抗瘤作用.
- 增加的TXNIP通过破坏UFBP1相互作用来抑制H4 UFMylation,影响cMYC染色体结合.
- 治疗JQ1诱导癌细胞的休眠状态,增加P27的稳定性,并赋予对铁亡的敏感性.
结论:
- TXNIP是JQ1抗瘤活性的关键媒介,影响表观遗传调节和细胞周期控制.
- BET抑制诱导癌细胞休眠,可以通过铁灭诱导剂克服,这表明了新的治疗策略.
- 这些发现提供了对蛋白质UFMylation和cMYC活性对BET抑制剂反应的调节的见解.
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