The mitochondrial type IB topoisomerase drives mitochondrial translation and carcinogenesis

• Published in: Nature communications Vol. 10; no. 1; pp. 83 - 13
• Main Authors: Baechler, S. A., Factor, V. M., Dalla Rosa, I., Ravji, A., Becker, D., Khiati, S., Miller Jenkins, L. M., Lang, M., Sourbier, C., Michaels, S. A., Neckers, L. M., Zhang, H. L., Spinazzola, A., Huang, S. N., Marquardt, J. U., Pommier, Y.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08.01.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/106; 13/109; 13/31; 13/51; 14; 14/19; 14/28; 38/91; 45/29; 59/5; 631/443/319; 631/443/319/333; 631/67; 631/67/1504; 631/67/2327; 64; 64/60; Animal models; Animals; Cancer; Carcinogenesis; Carcinogenesis - pathology; Carcinogens; Carcinogens - toxicity; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - mortality; Carcinoma, Hepatocellular - pathology; Cell Nucleus - metabolism; Cell Proliferation; Colon; Colon cancer; Datasets as Topic; DNA Topoisomerases, Type I - genetics; DNA Topoisomerases, Type I - metabolism; DNA, Mitochondrial - genetics; DNA, Mitochondrial - isolation & purification; Drug development; Energy Metabolism; Female; Fibroblasts; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Glycolysis; HCT116 Cells; Hepatocellular carcinoma; Human health and pathology; Humanities and Social Sciences; Humans; Life Sciences; Liver; Liver - cytology; Liver - metabolism; Liver - pathology; Liver cancer; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver Neoplasms - mortality; Liver Neoplasms - pathology; Liver Neoplasms, Experimental - chemically induced; Liver Neoplasms, Experimental - genetics; Liver Neoplasms, Experimental - metabolism; Liver Neoplasms, Experimental - pathology; Male; Mice; Mice, Knockout; Mice, Nude; Mitochondria; Mitochondria - metabolism; Mitochondria - pathology; Mitochondrial DNA; multidisciplinary; Oxidative phosphorylation; Phosphorylation; Prognosis; Protein Biosynthesis; Science; Science (multidisciplinary); Survival Analysis; Transcription; Translation; Tumors; Xenograft Model Antitumor Assays; Protein Biosynthesis; Carcinoma; Prognosis; Cell Proliferation; Mitochondrial; Humans; Liver; Male; Gene Expression Profiling; Liver Neoplasms; Carcinogenesis; Nude; Carcinogens; fibroblasts; Female; Datasets as Topic; HCT116 Cells; Experimental; mitochondria; Gene Expression Regulation; glycolysis; Knockout; Hepatocellular; Xenograft Model Antitumor Assays; Animals; Energy Metabolism; DNA; Survival Analysis; Type I; Mice; Neoplastic; DNA Topoisomerases; Cell Nucleus
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-07922-3

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. TOP1MT is a topoisomerase that is localised to mitochondria. Here, the authors show that TOP1MT has a tumor promoting role in hepatocellular carcinoma by supporting mitochondrial translation and that its deficiency limits tumorigenicity.