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DAF-16/FOXO targets genes that regulate tumor growth in Caenorhabditis elegans

Abstract

Cancer is an age-related disease, and inhibiting insulin/insulin-like growth factor 1 (IGF-1) signaling extends lifespan and increases tumor resistance in C. elegans and mammals. To investigate how the insulin/IGF-1 pathway couples these two processes, we analyzed putative transcriptional targets of the C. elegans FOXO transcription factor DAF-16, which promotes both longevity and tumor resistance. Twenty-nine of 734 genes tested influenced germline-tumor cell proliferation or p53-dependent apoptosis. About half of these genes also affected normal aging, thereby linking these two processes mechanistically. Many of these 29 genes are orthologs of known human tumor suppressors or oncogenes, suggesting that others may be as well. Our findings implicate nuclear-pore modification in p53-dependent cell death, because inhibiting nuclear-pore genes that are upregulated by DAF-16 blocks p53-dependent cell death in the tumor, but not normal, p53-independent, germline cell death.

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Figure 1: DAF-16/FOXO target genes that inhibit the growth of gld-1 tumors.
Figure 2: DAF-16/FOXO target genes that stimulate the growth of gld-1 tumors.
Figure 3: Inhibiting nuclear pore proteins specifically prevents the germline apoptosis triggered by daf-2 mutation or genotoxic stress.
Figure 4: DCT-11 antagonizes the DNA-damage cell death pathway to inhibit germ cell death in gld-1(–) mutants.

References

  1. Francis, R., Barton, M.K., Kimble, J. & Schedl, T. gld-1, a tumor suppressor gene required for oocyte development in Caenorhabditis elegans. Genetics 139, 579–606 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Pinkston, J.M., Garigan, D., Hansen, M. & Kenyon, C. Mutations that increase the life span of C. elegans inhibit tumor growth. Science 313, 971–975 (2006).

    Article  CAS  Google Scholar 

  3. Ramsey, M.M. et al. Growth hormone-deficient dwarf animals are resistant to dimethylbenzanthracine (DMBA)-induced mammary carcinogenesis. Endocrinology 143, 4139–4142 (2002).

    Article  CAS  Google Scholar 

  4. Paik, J.H. et al. FoxOs are lineage-restricted redundant tumor suppressors and regulate endothelial cell homeostasis. Cell 128, 309–323 (2007).

    Article  CAS  Google Scholar 

  5. Murphy, C.T. et al. Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans. Nature 424, 277–283 (2003).

    Article  CAS  Google Scholar 

  6. McElwee, J., Bubb, K. & Thomas, J.H. Transcriptional outputs of the Caenorhabditis elegans forkhead protein DAF-16. Aging Cell 2, 111–121 (2003).

    Article  CAS  Google Scholar 

  7. Oh, S.W. et al. Identification of direct DAF-16 targets controlling longevity, metabolism and diapause by chromatin immunoprecipitation. Nat. Genet. 38, 251–257 (2006).

    Article  Google Scholar 

  8. Lee, S.S., Kennedy, S., Tolonen, A.C. & Ruvkun, G. DAF-16 target genes that control C. elegans life-span and metabolism. Science 300, 644–647 (2003).

    Article  CAS  Google Scholar 

  9. Ren, C. et al. RTVP-1, a tumor suppressor inactivated by methylation in prostate cancer. Cancer Res. 64, 969–976 (2004).

    Article  CAS  Google Scholar 

  10. Fahrenkrog, B. The nuclear pore complex, nuclear transport, and apoptosis. Can. J. Physiol. Pharmacol. 84, 279–286 (2006).

    Article  CAS  Google Scholar 

  11. Kasper, L.H. et al. CREB binding protein interacts with nucleoporin-specific FG repeats that activate transcription and mediate NUP98-HOXA9 oncogenicity. Mol. Cell. Biol. 19, 764–776 (1999).

    Article  CAS  Google Scholar 

  12. Schumacher, B., Hofmann, K., Boulton, S. & Gartner, A. The C. elegans homolog of the p53 tumor suppressor is required for DNA damage-induced apoptosis. Curr. Biol. 11, 1722–1727 (2001).

    Article  CAS  Google Scholar 

  13. Wechsler, D.S., Shelly, C.A., Petroff, C.A. & Dang, C.V. MXI1, a putative tumor suppressor gene, suppresses growth of human glioblastoma cells. Cancer Res. 57, 4905–4912 (1997).

    CAS  PubMed  Google Scholar 

  14. Qi, J. et al. CASK inhibits ECV304 cell growth and interacts with Id1. Biochem. Biophys. Res. Commun. 328, 517–521 (2005).

    Article  CAS  Google Scholar 

  15. Milner, A.E., Grand, R.J., Vaughan, A.T., Armitage, R.J. & Gregory, C.D. Differential effects of BCL-2 on survival and proliferation of human B-lymphoma cells following gamma-irradiation. Oncogene 15, 1815–1822 (1997).

    Article  CAS  Google Scholar 

  16. Delpuech, O. et al. Induction of Mxi1-SR{alpha} by FOXO3a contributes to repression of Myc-dependent gene expression. Mol Cell Biol (2007).

  17. Modur, V., Nagarajan, R., Evers, B.M. & Milbrandt, J. FOXO proteins regulate tumor necrosis factor-related apoptosis inducing ligand expression. Implications for PTEN mutation in prostate cancer. J. Biol. Chem. 277, 47928–47937 (2002).

    Article  CAS  Google Scholar 

  18. Zhou, L. et al. Overexpression of LAPTM4B–35 closely correlated with clinicopathological features and post-resectional survival of gallbladder carcinoma. Eur. J. Cancer 43, 809–815 (2007).

    Article  CAS  Google Scholar 

  19. Li, C.M. et al. PEG10 is a c-MYC target gene in cancer cells. Cancer Res. 66, 665–672 (2006).

    Article  CAS  Google Scholar 

  20. Madi, L. et al. The A3 adenosine receptor is highly expressed in tumor versus normal cells: potential target for tumor growth inhibition. Clin. Cancer Res. 10, 4472–4479 (2004).

    Article  CAS  Google Scholar 

  21. Ohana, G., Bar-Yehuda, S., Barer, F. & Fishman, P. Differential effect of adenosine on tumor and normal cell growth: focus on the A3 adenosine receptor. J. Cell. Physiol. 186, 19–23 (2001).

    Article  CAS  Google Scholar 

  22. Shimada, H. et al. Analysis of genes under the downstream control of the t(8;21) fusion protein AML1–MTG8: overexpression of the TIS11b (ERF-1, cMG1) gene induces myeloid cell proliferation in response to G-CSF. Blood 96, 655–663 (2000).

    CAS  PubMed  Google Scholar 

  23. Singh, A.P., Chaturvedi, P. & Batra, S.K. Emerging roles of MUC4 in cancer: a novel target for diagnosis and therapy. Cancer Res. 67, 433–436 (2007).

    Article  CAS  Google Scholar 

  24. Garigan, D. et al. Genetic analysis of tissue aging in Caenorhabditis elegans: a role for heat-shock factor and bacterial proliferation. Genetics 161, 1101–1112 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Tyner, S.D. et al. p53 mutant mice that display early ageing-associated phenotypes. Nature 415, 45–53 (2002).

    Article  CAS  Google Scholar 

  26. Futreal, P.A. et al. A census of human cancer genes. Nat. Rev. Cancer 4, 177–183 (2004).

    Article  CAS  Google Scholar 

  27. Lawless, J.F. Models and Methods for Lifetime Data (Wiley, New York, 1998).

    Google Scholar 

  28. Kenyon, C. & Murphy, C.T. Enrichment of regulatory motifs upstream of predicted DAF-16 targets. Nat Genet 38, 397–8 ; author reply 398 (2006).

    Article  CAS  Google Scholar 

  29. Alcedo, J. & Kenyon, C. Regulation of C. elegans longevity by specific gustatory and olfactory neurons. Neuron 41, 45–55 (2004).

    Article  CAS  Google Scholar 

  30. Nakielny, S. & Dreyfuss, G. Transport of proteins and RNAs in and out of the nucleus. Cell 99, 677–690 (1999).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank S. Henis-Korenblit, M. Hansen and N. Gosse for careful reading of the text, and the Caenorhabditis Genetics Center and the C. elegans Gene Knockout Consortium for providing strains. This work was supported by US National Institutes of Health funding to C.K. J.P.-G. was supported by University of California San Francisco's Chancellor's fellowship. C.K. is an American Cancer Society Research Professor and a founder and director of Elixir Pharmaceuticals.

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J.P.-G. carried out all the experiments. C.K. helped to design the experiments and write the paper.

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Correspondence to Cynthia Kenyon.

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The authors declare no competing financial interests.

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Supplementary Figures 1–5, Supplementary Tables 1–5 (PDF 2280 kb)

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Pinkston-Gosse, J., Kenyon, C. DAF-16/FOXO targets genes that regulate tumor growth in Caenorhabditis elegans. Nat Genet 39, 1403–1409 (2007). https://doi.org/10.1038/ng.2007.1

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