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Oct1 loss of function induces a coordinate metabolic shift that opposes tumorigenicity

Nature Cell Biology volume 11, pages 320–327 (2009)Cite this article

Abstract

Cancer cells frequently undergo a shift from oxidative to glycolytic metabolism1. Although there is interest in targeting metabolism as a form of cancer therapy, this area still remains in its infancy. Using cells, embryos and adult animals, we show here that loss of the widely expressed transcription factor Oct1 induces a coordinated metabolic shift: mitochondrial activity and amino acid oxidation are increased, while glucose metabolism is reduced. Altered expression of direct Oct1 targets encoding metabolic regulators provides a mechanistic underpinning to these results. We show that these metabolic changes directly oppose tumorigenicity. Collectively, our findings show that Oct1, the genes it regulates and the pathways these genes affect could be used as targets for new modes of cancer therapy.

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Figure 1: Oct1−/− MEFs and embryos use less glucose, yet are more metabolically active.
Figure 2: The metabolic profile of Oct1−/− MEFs and Oct1+/− mice is distinct from their wild-type (WT) counterparts.
Figure 3: Oct1 deficiency alters metabolism in adult cells.
Figure 4: Metabolic genes are differentially expressed in Oct1−/− MEFs.
Figure 5: Oct1-deficiency decreases tumorigenic potential.

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Acknowledgements

We are indebted to J. Kaplan for helpful suggestions during the formative stages of this work. We thank D. Ayer and J. Rutter for critical reading of the manuscript. C. Cheng provided the H-RasV12 retroviral construct and T. Jacks provided p53−/− mice. We thank D. Abel and J. Soto for use of laboratory equipment and N. Chandler and the EM core facility for TEM. We thank P. Sharp and members of his laboratory for invaluable assistance. We also thank D. Stillman, J. Rutter, S. Lessnick and J. Shaw for helpful advice and reagents. This work was supported by a Centers of Excellence Grant in Molecular Haematology from the National Institutes of Health and a grant from the American Cancer Society to D.T.

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Authors and Affiliations

  1. Department of Pathology, University of Utah School of Medicine, Salt Lake City, 84112, Utah, USA

    Arvind Shakya & Dean Tantin

  2. Department of Medicine, University of Utah School of Medicine, Salt Lake City, 84112, Utah, USA

    Robert Cooksey & Donald A. McClain

  3. Health Sciences Center Core Research Facilities, University of Utah School of Medicine, Salt Lake City, 84112, Utah, USA

    James E. Cox

  4. Harvard Radiation Oncology Program, Boston, 02115, Massachusetts, USA

    Victoria Wang

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  1. Arvind Shakya
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  4. Victoria Wang
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Contributions

A.S. and D.T. designed the study. A.S. along with D.T., R.C. and J.C. performed the experiments. D.T., V.W. and D.M. provided reagents. A.S. and D.T. wrote the manuscript.

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Correspondence to Dean Tantin.

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Shakya, A., Cooksey, R., Cox, J. et al. Oct1 loss of function induces a coordinate metabolic shift that opposes tumorigenicity. Nat Cell Biol 11, 320–327 (2009). https://doi.org/10.1038/ncb1840

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