线粒体DNA
线粒体
癌症研究
生物
癌变
翻译(生物学)
癌症
氧化磷酸化
细胞生物学
基因
遗传学
生物化学
信使核糖核酸
作者
Simone A. Baechler,Valentine Factor,Ilaria Dalla Rosa,Azhar Ravji,Doreen Becker,Salim Khiati,Lisa M. Miller Jenkins,Martin Lang,Carole Sourbier,Stephanie A. Michaels,Len Neckers,H. L. Zhang,Antonella Spinazzola,Shar-yin N. Huang,Jens U. Marquardt,Yves Pommier
标识
DOI:10.1038/s41467-018-07922-3
摘要
Mitochondrial topoisomerase IB (TOP1MT) is a nuclear-encoded topoisomerase, exclusively localized to mitochondria, which resolves topological stress generated during mtDNA replication and transcription. Here, we report that TOP1MT is overexpressed in cancer tissues and demonstrate that TOP1MT deficiency attenuates tumor growth in human and mouse models of colon and liver cancer. Due to their mitochondrial dysfunction, TOP1MT-KO cells become addicted to glycolysis, which limits synthetic building blocks and energy supply required for the proliferation of cancer cells in a nutrient-deprived tumor microenvironment. Mechanistically, we show that TOP1MT associates with mitoribosomal subunits, ensuring optimal mitochondrial translation and assembly of oxidative phosphorylation complexes that are critical for sustaining tumor growth. The TOP1MT genomic signature profile, based on Top1mt-KO liver cancers, is correlated with enhanced survival of hepatocellular carcinoma patients. Our results highlight the importance of TOP1MT for tumor development, providing a potential rationale to develop TOP1MT-targeted drugs as anticancer therapies.
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