Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

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

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

References

  1. Kim, J. W. & Dang, C. V. Cancer's molecular sweet tooth and the Warburg effect. Cancer Res. 66, 8927–8930 (2006).

    Article  CAS  Google Scholar 

  2. Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57–70 (2000).

    Article  CAS  Google Scholar 

  3. Warburg, O. On the origin of cancer cells. Science 123, 309–314 (1956).

    Article  CAS  Google Scholar 

  4. Bonnet, S. et al. A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell 11, 37–51 (2007).

    Article  CAS  Google Scholar 

  5. Christofk, H. R. et al. The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature 452, 230–233 (2008).

    Article  CAS  Google Scholar 

  6. Herr, W. & Cleary, M. A. The POU domain: versatility in transcriptional regulation by a flexible two-in-one DNA-binding domain. Genes Dev. 9, 1679–1693 (1995).

    Article  CAS  Google Scholar 

  7. Ryan, A. K. & Rosenfeld, M. G. POU domain family values: flexibility, partnerships, and developmental codes. Genes Dev. 11, 1207–1225 (1997).

    Article  CAS  Google Scholar 

  8. Sive, H. L. & Roeder, R. G. Interaction of a common factor with conserved promoter and enhancer sequences in histone H2B, immunoglobulin, and U2 small nuclear RNA (snRNA) genes. Proc. Natl Acad. Sci. USA 83, 6382–6386 (1986).

    Article  CAS  Google Scholar 

  9. Fletcher, C., Heintz, N. & Roeder, R. G. Purification and characterization of OTF-1, a transcription factor regulating cell cycle expression of a human histone H2b gene. Cell 51, 773–781 (1987).

    Article  CAS  Google Scholar 

  10. Gunderson, S. I. et al. Binding of transcription factors to the promoter of the human U1 RNA gene studied by footprinting. J. Biol. Chem. 263, 17603–17610 (1988).

    CAS  PubMed  Google Scholar 

  11. Bergman, Y., Rice, D., Grosschedl, R. & Baltimore, D. Two regulatory elements for immunoglobulin kappa light chain gene expression. Proc. Natl Acad. Sci. USA 81, 7041–7045 (1984).

    Article  CAS  Google Scholar 

  12. Ephrussi, A., Church, G. M., Tonegawa, S. & Gilbert, W. B lineage--specific interactions of an immunoglobulin enhancer with cellular factors in vivo. Science 227, 134–140 (1985).

    Article  CAS  Google Scholar 

  13. Gillies, S. D., Morrison, S. L., Oi, V. T. & Tonegawa, S. A tissue-specific transcription enhancer element is located in the major intron of a rearranged immunoglobulin heavy chain gene. Cell 33, 717–728 (1983).

    Article  CAS  Google Scholar 

  14. Wang, V. E., Tantin, D., Chen, J. & Sharp, P. A. B cell development and immunoglobulin transcription in Oct-1-deficient mice. Proc. Natl Acad. Sci. USA 101, 2005–2010 (2004).

    Article  CAS  Google Scholar 

  15. Wang, V. E., Schmidt, T., Chen, J., Sharp, P. A. & Tantin, D. Embryonic lethality, decreased erythropoiesis, and defective octamer-dependent promoter activation in Oct-1-deficient mice. Mol. Cell Biol. 24, 1022–1032 (2004).

    Article  CAS  Google Scholar 

  16. Almeida, R. et al. OCT-1 is over-expressed in intestinal metaplasia and intestinal gastric carcinomas and binds to, but does not transactivate, CDX2 in gastric cells. J. Pathol. 207, 396–401 (2005).

    Article  CAS  Google Scholar 

  17. Jin, T. et al. Examination of POU homeobox gene expression in human breast cancer cells. Int. J. Cancer 81, 104–112 (1999).

    Article  CAS  Google Scholar 

  18. Qin, X. F. et al. Transformation by homeobox genes can be mediated by selective transcriptional repression. EMBO J. 13, 5967–5976 (1994).

    Article  CAS  Google Scholar 

  19. Reymann, S. & Borlak, J. Transcription profiling of lung adenocarcinomas of c-myc-transgenic mice: identification of the c-myc regulatory gene network. BMC Syst. Biol. 2, 46 (2008).

    Article  Google Scholar 

  20. Tantin, D., Schild-Poulter, C., Wang, V., Hache, R. J. & Sharp, P. A. The octamer binding transcription factor Oct-1 is a stress sensor. Cancer Res. 65, 10750–10758 (2005).

    Article  CAS  Google Scholar 

  21. Sakai, K., Hasumi, K. & Endo, A. Inactivation of rabbit muscle glyceraldehyde-3-phosphate dehydrogenase by koningic acid. Biochim. Biophys. Acta 952, 297–303 (1988).

    Article  CAS  Google Scholar 

  22. Stryer, L. Biochemistry (W. H. Freeman and Company, 2006).

    Google Scholar 

  23. Chen, X. et al. Integration of external signaling pathways with the core transcriptional network in embryonic stem cells. Cell 133, 1106–1117 (2008).

    Article  CAS  Google Scholar 

  24. Kondoh, H. et al. A high glycolytic flux supports the proliferative potential of murine embryonic stem cells. Antioxid. Redox Signal. 9, 293–299 (2007).

    Article  CAS  Google Scholar 

  25. Glahn, F. et al. Cadmium, cobalt and lead cause stress response, cell cycle deregulation and increased steroid as well as xenobiotic metabolism in primary normal human bronchial epithelial cells which is coordinated by at least nine transcription factors. Arch. Toxicol. 82, 513–524 (2008).

    Article  CAS  Google Scholar 

  26. Wu, Z. et al. Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell 98, 115–124 (1999).

    Article  CAS  Google Scholar 

  27. Hicks, G. G., Egan, S. E., Greenberg, A. H. & Mowat, M. Mutant p53 tumour suppressor alleles release ras-induced cell cycle growth arrest. Mol. Cell. Biol. 11, 1344–1352 (1991).

    Article  CAS  Google Scholar 

  28. Jacks, T. et al. Tumor spectrum analysis in p53-mutant mice. Curr. Biol. 4, 1–7 (1994).

    Article  CAS  Google Scholar 

  29. Matoba, S. et al. p53 regulates mitochondrial respiration. Science 312, 1650–1653 (2006).

    Article  CAS  Google Scholar 

  30. Debidda, M., Williams, D. A. & Zheng, Y. Rac1 GTPase regulates cell genomic stability and senescence. J. Biol. Chem. 281, 38519–38528 (2006).

    Article  CAS  Google Scholar 

  31. Heiss, E. H., Schilder, Y. D. & Dirsch, V. M. Chronic Treatment with Resveratrol Induces Redox Stress- and Ataxia Telangiectasia-mutated (ATM)-dependent Senescence in p53-positive Cancer Cells. J. Biol. Chem. 282, 26759–26766 (2007).

    Article  CAS  Google Scholar 

  32. Zheng, L., Roeder, R. G. & Luo, Y. S. phase activation of the histone H2B promoter by OCA-S., a coactivator complex that contains GAPDH as a key component. Cell 114, 255–266 (2003).

    Article  CAS  Google Scholar 

  33. Hafstad, A. D., Solevag, G. H., Severson, D. L., Larsen, T. S. & Aasum, E. Perfused hearts from Type 2 diabetic (db/db) mice show metabolic responsiveness to insulin. Am. J. Physiol. Heart Circ. Physiol. 290, 1763–1769 (2006).

    Article  Google Scholar 

  34. McClain, D. A., Hazel, M., Parker, G. & Cooksey, R. C. Adipocytes with increased hexosamine flux exhibit insulin resistance, increased glucose uptake, and increased synthesis and storage of lipid. Am. J. Physiol. Endocrinol. Metab. 288, 973–979 (2005).

    Article  Google Scholar 

  35. Boyd, K. E. & Farnham, P. J. Coexamination of site-specific transcription factor binding and promoter activity in living cells. Mol. Cell Biol. 19, 8393–8399 (1999).

    Article  CAS  Google Scholar 

  36. Melgar, S. et al. Mice with experimental colitis show an altered metabolism with decreased metabolic rate. Am. J. Physiol. Gastrointest. Liver Physiol. 292, 165–172 (2007).

    Article  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

Authors

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.

Corresponding author

Correspondence to Dean Tantin.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

Supplementary Information (PDF 1189 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb1840

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing