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线粒体局部化的MBD2c促进mtDNA转录和耐药性

Yijie Hao^1,2, Zilong Zhou^1,2,3, Rui Liu^1,2

¹Department of General Surgery, Anhui Provincial Hospital, the First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, China.

Nature chemical biology

|November 28, 2024

概括

甲基-CpG结合域蛋白2c (MBD2c) 进入线粒体,以促进三阴性乳腺癌 (TNBC) 中的线粒体DNA (mtDNA) 转录和呼吸. 这一发现揭示了与癌症代谢和药物耐药性的新表观遗传联系.

科学领域:

线粒体生物学线粒体生物学
表观遗传学在表观遗传学中,表观遗传学是指表观遗传学.
癌症研究癌症研究

背景情况:

线粒体拥有独特的基因组 (mtDNA),对细胞呼吸至关重要.
对mtDNA转录的调节及其在癌症中的作用尚未完全理解.
甲基-CpG结合域 (MBD) 蛋白质是已知的核表观遗传调节剂,但它们的线粒体功能尚未被探索.

研究的目的:

研究MBD蛋白在线粒体DNA (mtDNA) 转录中的作用.
探索MBD2c拼接变体在线粒体调节中的功能.
确定MBD2c对三阴性乳腺癌 (TNBC) 细胞代谢和耐药性的影响.

主要方法:

研究了MBD2c在TNBC细胞中的亚细胞局部.
评估了MBD2c与mtDNA的结合及其与SIRT3和TFAM的相互作用.
分析了MBD2c对mtDNA基因表达和线粒体呼吸的影响.
评估了MBD2c在西斯普拉丁耐药性和TNBC细胞增殖中的作用.

主要成果:

发现MBD2c拼接变体转移到TNBC细胞中的线粒体.
MBD2c与mtDNA结合并与SIRT3相互作用,导致TFAM激活和增强mtDNA转录.
通过cisplatin抑制的MBD2c恢复了线粒体基因表达和呼吸.
在TNBC细胞中,MBD2c表达增强了药物耐药性和增殖.

结论:

在TNBC中,MBD2c积极调节mtDNA转录和线粒体呼吸.
这项研究揭示了MBD2c介导的表观遗传调节 (通过脱甲基化) 与癌细胞代谢之间的新鲜联系.
在增强耐药性的MBD2c的作用表明潜在的治疗目标克服TNBC的耐药性.

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