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The microRNA-182-PDK4 axis regulates lung tumorigenesis by modulating pyruvate dehydrogenase and lipogenesis

Oncogene volume 36, pages 989–998 (2017)Cite this article

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Abstract

Reprogrammed metabolism is one of the hallmarks of cancer. The dysregulation of glycolysis in cancer has been heavily studied. However, it remains largely unclear how other metabolic processes are regulated in cancer cells. Here we show that microRNA-182 (miR-182) suppresses pyruvate dehydrogenase (PDH) kinase 4 (PDK4) and promotes lung tumorigenesis. miR-182 is dysregulated and inversely correlated with PDK4 in human lung adenocarcinomas. The miR-182-PDK4 axis regulates lung cancer cell growth by modulating the activity of PDH, the gatekeeping enzyme of pyruvate flux into acetyl-CoA, and subsequently de novo lipogenesis of cancer cells. Suppression of lipogenesis by silencing ATP citrate lyase (ACLY) and fatty acid synthase (FASN) or by chemical inhibitors diminishes the effects of miR-182-PDK4 in tumor growth. Alteration of de novo lipogenesis also affects reactive oxygen species (ROS) production and the downstream JNK signaling pathway. Hence, our work suggests that the miR-182-PDK4 axis is a crucial regulator of cancer cell metabolism and a potential target for antitumor therapy.

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Acknowledgements

We thank Dr Weihong Sun at the Tissue Bank of the Institute of Health Sciences for technical support. The study was funded by grants from the Ministry of Science and Technology of China (2011CB510105, 2012ZX09506-001-005 and 2013CB910904), National Natural Science Foundation of China (81430070, 81222032 and 31371409), Chinese Academy of Sciences (XDA01040402) and Science and Technology Commission of Shanghai Municipality (14431900800).

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Authors and Affiliations

  1. The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine, Shanghai, China

    G Li, J Hu, R Lei & G Hu

  2. The Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China

    M Li & H Yin

  3. Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China

    H Xiong

  4. The State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China

    H Ji

  5. Department of Pathology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China

    Q Wei

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Li, G., Li, M., Hu, J. et al. The microRNA-182-PDK4 axis regulates lung tumorigenesis by modulating pyruvate dehydrogenase and lipogenesis. Oncogene 36, 989–998 (2017). https://doi.org/10.1038/onc.2016.265

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