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.

  • Opinion
  • Published:

Yeast as a model system for anticancer drug discovery

Abstract

Yeast is widely used as a model organism for investigating many aspects of eukaryotic cell biology. It combines a high level of conservation between its cellular processes and those of mammalian cells with advantages such as simple growth requirements, rapid cell division, ease of genetic manipulation and a wealth of experimental tools for genome-wide analysis of biological functions. How can these advantages be put to use in anticancer drug discovery?

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: Target-based screens for anticancer drugs using yeast.
Figure 2: Functions of yeast Sir2 and its mammalian homologue, SIRT1.
Figure 3: Example of a pathway-based screen in yeast.
Figure 4: Effects of a bub3Δ context-specific growth inhibitor on yeast strains deficient in components of the mitotic-checkpoint pathway.

Similar content being viewed by others

References

  1. Marton, M. J. et al. Drug target validation and identification of secondary drug target effects using DNA microarrays. Nature Med. 4, 1293–1301 (1998).

    Article  CAS  PubMed  Google Scholar 

  2. Parsons, A. B. et al. Integration of chemical-genetic and genetic interaction data links bioactive compounds to cellular target pathways. Nature Biotechnol. 22, 62–69 (2004).

    Article  CAS  Google Scholar 

  3. Birrell, G. W. et al. A genome-wide screen in Saccharomyces cerevisiae for genes affecting UV radiation sensitivity. Proc. Natl Acad. Sci. USA 98, 12608–12613 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Tong, A. H. et al. Global mapping of the yeast genetic interaction network. Science 303, 808–813 (2004).

    Article  CAS  PubMed  Google Scholar 

  5. Lum, P. Y. et al. Discovering modes of action for therapeutic compounds using a genome-wide screen of yeast heterozygotes. Cell 116, 121–137 (2004).

    Article  CAS  PubMed  Google Scholar 

  6. Ubersax, J. A. et al. Targets of the cyclin-dependent kinase Cdk1. Nature 425, 859–864 (2003).

    Article  CAS  PubMed  Google Scholar 

  7. von Mering, C. et al. Comparative assessment of large-scale data sets of protein–protein interactions. Nature 417, 399–403 (2002).

    Article  CAS  PubMed  Google Scholar 

  8. Hartwell, L. H. et al. Integrating genetic approaches into the discovery of anticancer drugs. Science 278, 1064–1068 (1997).

    Article  CAS  PubMed  Google Scholar 

  9. Gaber, R. F. et al. The yeast gene ERG6 is required for normal membrane function but is not essential for biosynthesis of the cell-cycle-sparking sterol. Mol. Cell. Biol. 9, 3447–3456 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Balzi, E. & Goffeau, A. Yeast multidrug resistance: the PDR network. J. Bioenerg. Biomembr. 27, 71–76 (1995).

    Article  CAS  PubMed  Google Scholar 

  11. Tugendreich, S. et al. A streamlined process to phenotypically profile heterologous cDNAs in parallel using yeast cell-based assays. Genome Res. 11, 1899–1912 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Perkins, E. et al. Novel inhibitors of poly(ADP-ribose) polymerase/PARP1 and PARP2 identified using a cell-based screen in yeast. Cancer Res. 61, 4175–4183 (2001).

    CAS  PubMed  Google Scholar 

  13. Althaus, F. R. & Richter, C. ADP-ribosylation of proteins. Enzymology and biological significance. Mol. Biol. Biochem. Biophys. 37, 1–237 (1987).

    CAS  PubMed  Google Scholar 

  14. Tentori, L. et al. Systemic administration of GPI 15427, a novel poly(ADP-ribose) polymerase-1 inhibitor, increases the antitumor activity of temozolomide against intracranial melanoma, glioma, lymphoma. Clin. Cancer Res. 9, 5370–5379 (2003).

    CAS  PubMed  Google Scholar 

  15. Ortega, S., Malumbres, M. & Barbacid, M. Cyclin D-dependent kinases, INK4 inhibitors and cancer. Biochim. Biophys. Acta 1602, 73–87 (2002).

    CAS  PubMed  Google Scholar 

  16. Polyak, K. et al. p27Kip1, a cyclin–Cdk inhibitor, links transforming growth factor-β and contact inhibition to cell cycle arrest. Genes Dev. 8, 9–22 (1994).

    Article  CAS  PubMed  Google Scholar 

  17. Quelle, D. E. et al. Cloning and characterization of murine p16INK4a and p15INK4b genes. Oncogene 11, 635–645 (1995).

    CAS  PubMed  Google Scholar 

  18. Liu, G. et al. A Phase II trial of flavopiridol (NSC #649890) in patients with previously untreated metastatic androgen-independent prostate cancer. Clin. Cancer Res. 10, 924–928 (2004).

    Article  CAS  PubMed  Google Scholar 

  19. Moorthamer, M. et al. The p16INK4A protein and flavopiridol restore yeast cell growth inhibited by Cdk4. Biochem. Biophys. Res. Commun. 250, 791–797 (1998).

    Article  CAS  PubMed  Google Scholar 

  20. Scorrano, L. & Korsmeyer, S. J. Mechanisms of cytochrome c release by proapoptotic BCL-2 family members. Biochem. Biophys. Res. Commun. 304, 437–444 (2003).

    Article  CAS  PubMed  Google Scholar 

  21. Xu, Q. & Reed, J. C. Bax inhibitor-1, a mammalian apoptosis suppressor identified by functional screening in yeast. Mol. Cell 1, 337–346 (1998).

    Article  CAS  PubMed  Google Scholar 

  22. Hake, S. B., Xiao, A. & Allis, C. D. Linking the epigenetic 'language' of covalent histone modifications to cancer. Br. J. Cancer 90, 761–769 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Li, E., Bestor, T. H. & Jaenisch, R. Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell 69, 915–926 (1992).

    Article  CAS  PubMed  Google Scholar 

  24. Shore, D., Squire, M. & Nasmyth, K. A. Characterization of two genes required for the position-effect control of yeast mating-type genes. EMBO J. 3, 2817–2823 (1984).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Brachmann, C. B. et al. The SIR2 gene family, conserved from bacteria to humans, functions in silencing, cell cycle progression, and chromosome stability. Genes Dev. 9, 2888–2902 (1995).

    Article  CAS  PubMed  Google Scholar 

  26. Singer, M. S. et al. Identification of high-copy disruptors of telomeric silencing in Saccharomyces cerevisiae. Genetics 150, 613–632 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Feng, Q. et al. Methylation of H3-lysine 79 is mediated by a new family of HMTases without a SET domain. Curr. Biol. 12, 1052–1058 (2002).

    Article  CAS  PubMed  Google Scholar 

  28. Rine, J. & Herskowitz, I. Four genes responsible for a position effect on expression from HML and HMR in Saccharomyces cerevisiae. Genetics 116, 9–22 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Vaziri, H. et al. hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase. Cell 107, 149–159 (2001).

    Article  CAS  PubMed  Google Scholar 

  30. Luo, J. et al. Negative control of p53 by Sir2α promotes cell survival under stress. Cell 107, 137–148 (2001).

    Article  CAS  PubMed  Google Scholar 

  31. Bereshchenko, O. R., Gu, W. & Dalla-Favera, R. Acetylation inactivates the transcriptional repressor BCL6. Nature Genet. 32, 606–613 (2002).

    Article  CAS  PubMed  Google Scholar 

  32. Pasqualucci, L. et al. Mutations of the BCL6 proto-oncogene disrupt its negative autoregulation in diffuse large B-cell lymphoma. Blood 101, 2914–2923 (2003).

    Article  CAS  PubMed  Google Scholar 

  33. van Leeuwen, F. & Gottschling, D. E. Assays for gene silencing in yeast. Methods Enzymol. 350, 165–186 (2002).

    Article  CAS  PubMed  Google Scholar 

  34. Bedalov, A. et al. Identification of a small molecule inhibitor of Sir2p. Proc. Natl Acad. Sci. USA 98, 15113–15118 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Bedalov, A. et al. NAD+-dependent deacetylase Hst1p controls biosynthesis and cellular NAD+ levels in Saccharomyces cerevisiae. Mol. Cell. Biol. 23, 7044–7054 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Hirao, M. et al. Identification of selective inhibitors of NAD+-dependent deacetylases using phenotypic screens in yeast. J. Biol. Chem. 278, 52773–52782 (2003).

    Article  CAS  PubMed  Google Scholar 

  37. Posakony, J. et al. Inhibitors of Sir2: evaluation of splitomicin analogues. J. Med. Chem. (in the press).

  38. Peltomaki, P. Deficient DNA mismatch repair: a common etiologic factor for colon cancer. Hum. Mol. Genet. 10, 735–740 (2001).

    Article  CAS  PubMed  Google Scholar 

  39. Esteller, M. Cancer epigenetics: DNA methylation and chromatin alterations in human cancer. Adv. Exp. Med. Biol. 532, 39–49 (2003).

    Article  CAS  PubMed  Google Scholar 

  40. Weinberg, R. A. The retinoblastoma protein and cell cycle control. Cell 81, 323–330 (1995).

    Article  CAS  PubMed  Google Scholar 

  41. Torrance, C. J. et al. Use of isogenic human cancer cells for high-throughput screening and drug discovery. Nature Biotechnol. 19, 940–945 (2001).

    Article  CAS  Google Scholar 

  42. Dunstan, H. M. et al. Cell-based assays for identification of novel double-strand break-inducing agents. J. Natl Cancer Inst. 94, 88–94 (2002).

    Article  CAS  PubMed  Google Scholar 

  43. Cahill, D. P. et al. Mutations of mitotic checkpoint genes in human cancers. Nature 392, 300–303 (1998).

    Article  CAS  PubMed  Google Scholar 

  44. Wassmann, K. & Benezra, R. Mitotic checkpoints: from yeast to cancer. Curr. Opin. Genet. Dev. 11, 83–90 (2001).

    Article  CAS  PubMed  Google Scholar 

  45. Hoyt, M. A., Totis, L. & Roberts, B. T. S. cerevisiae genes required for cell cycle arrest in response to loss of microtubule function. Cell 66, 507–517 (1991).

    Article  CAS  PubMed  Google Scholar 

  46. Griffith, E. C., Licitra, E. J. & Liu, J. O. Yeast three-hybrid system for detecting ligand-receptor interactions. Methods Enzymol. 328, 89–103 (2000).

    Article  CAS  PubMed  Google Scholar 

  47. Hughes, T. R. et al. Functional discovery via a compendium of expression profiles. Cell 102, 109–126 (2000).

    Article  CAS  PubMed  Google Scholar 

  48. Towbin, H. et al. Proteomics-based target identification: bengamides as a new class of methionine aminopeptidase inhibitors. J. Biol. Chem. 278, 52964–52971 (2003).

    Article  CAS  PubMed  Google Scholar 

  49. Momparler, R. L. Cancer epigenetics. Oncogene 22, 6479–6483 (2003).

    Article  CAS  PubMed  Google Scholar 

  50. Thiagalingam, S. et al. Histone deacetylases: unique players in shaping the epigenetic histone code. Ann. NY Acad. Sci. 983, 84–100 (2003).

    Article  CAS  PubMed  Google Scholar 

  51. Luo, J. et al. Negative control of p53 by Sir2α promotes cell survival under stress. Cell 107, 137–148 (2001).

    Article  CAS  PubMed  Google Scholar 

  52. Bereshchenko, O. R. et al. Acetylation inactivates the transcriptional repressor BCL6. Nature Genet. 32, 606–613 (2002).

    Article  CAS  PubMed  Google Scholar 

  53. Frye, R. 'SIRT8' expressed in thyroid cancer is actually SIRT7. Br. J. Cancer 87, 1479 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Panagopoulos, I. et al. Acute myeloid leukemia with inv(8)(p11q13). Leuk. Lymphoma 39, 651–656 (2000).

    Article  CAS  PubMed  Google Scholar 

  55. Emerling, B. M. et al. MLL5, a homolog of Drosophila trithorax located within a segment of chromosome band 7q22 implicated in myeloid leukemia. Oncogene 21, 4849–4854 (2002).

    Article  CAS  PubMed  Google Scholar 

  56. Varambally, S. et al. The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature 419, 624–629 (2002).

    Article  CAS  PubMed  Google Scholar 

  57. Keats, J. J. et al. In multiple myeloma, t(4;14)(p16;q32) is an adverse prognostic factor irrespective of FGFR3 expression. Blood 101, 1520–1529 (2003).

    Article  CAS  PubMed  Google Scholar 

  58. Feng, Q. et al. Methylation of H3-lysine 79 is mediated by a new family of HMTases without a SET domain. Curr. Biol. 12, 1052–1058 (2002).

    Article  CAS  PubMed  Google Scholar 

  59. van Leeuwen, F. et al. Dot1p modulates silencing in yeast by methylation of the nucleosome core. Cell 109, 745–756 (2002).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors wish to thank the members of the Simon group for helpful comments and members of the National Cancer Institute's Developmental Therapeutics Program for support in the NCI yeast screen.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Julian A. Simon.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

DATABASES

Entrez Gene

aurora-related kinase 1

BAK

BAX

BCL2

BCL6

BRCA1

BUB1

CDK4

INK4A

KIP1

p38

p53

PARP1

PTEN

RB

SIRT1

OMIM

hereditary non-polyposis colon cancer

FURTHER INFORMATION

NCI Yeast Anticancer Drug Screen web site

Rights and permissions

Reprints and permissions

About this article

Cite this article

Simon, J., Bedalov, A. Yeast as a model system for anticancer drug discovery. Nat Rev Cancer 4, 481–487 (2004). https://doi.org/10.1038/nrc1372

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc1372

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