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Metabolic reprogramming during TGFβ1-induced epithelial-to-mesenchymal transition

Oncogene volume 34, pages 3908–3916 (2015)Cite this article

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Abstract

Metastatic progression, including extravasation and micrometastatic outgrowth, is the main cause of cancer patient death. Recent studies suggest that cancer cells reprogram their metabolism to support increased proliferation through increased glycolysis and biosynthetic activities, including lipogenesis pathways. However, metabolic changes during metastatic progression, including alterations in regulatory gene expression, remain undefined. We show that transforming growth factor beta 1 (TGFβ1)-induced epithelial-to-mesenchymal transition (EMT) is accompanied by coordinately reduced enzyme expression required to convert glucose into fatty acids, and concomitant enhanced respiration. Overexpressed Snail1, a transcription factor mediating TGFβ1-induced EMT, was sufficient to suppress carbohydrate-responsive-element-binding protein (ChREBP, a master lipogenic regulator), and fatty acid synthase (FASN), its effector lipogenic gene. Stable FASN knockdown was sufficient to induce EMT, stimulate migration and extravasation in vitro. FASN silencing enhanced lung metastasis and death in vivo. These data suggest that a metabolic transition that suppresses lipogenesis and favors energy production is an essential component of TGFβ1-induced EMT and metastasis.

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Acknowledgements

We are grateful to Dr Xiuquan Luo for his aid in the BLI measurements and animal injections. This work was supported by DOE/NASA grant DE-FG-022179-18-21 and by NIH R01 CA139217 to DAB and NIH RO1 CA157996 and CPRIT RP130272 to RJD. We are grateful to the imaging core of the Simmons Cancer Center Support Grant (5P30 CA142543-03).

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Author notes

  1. L Jiang and L Xiao: These authors contributed equally to this work.

Authors and Affiliations

  1. Children's Medical Center Research Institute, Dallas, TX, USA

    L Jiang & R J Deberardinis

  2. Department of Pharmacology and Radiation Oncology, UT Southwestern Medical Center, Dallas, TX, USA,

    L Xiao, H Sugiura, X Huang & D A Boothman

  3. Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA,

    H Sugiura & M Kuro-o

  4. Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USA

    A Ali

  5. Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan

    M Kuro-o

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  1. L Jiang
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Correspondence to R J Deberardinis or D A Boothman.

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Jiang, L., Xiao, L., Sugiura, H. et al. Metabolic reprogramming during TGFβ1-induced epithelial-to-mesenchymal transition. Oncogene 34, 3908–3916 (2015). https://doi.org/10.1038/onc.2014.321

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  • DOI: https://doi.org/10.1038/onc.2014.321

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