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Targeting the ubiquitin system in cancer therapy

Nature volume 458, pages 438–444 (2009)Cite this article

Abstract

The ubiquitin system is a network of proteins dedicated to the ubiquitylation of cellular targets and the subsequent control of numerous cellular functions. The deregulation of components of this elaborate network leads to human pathogenesis, including the development of many types of tumour. Alterations in the ubiquitin system that occur during the initiation and progression of cancer are now being uncovered, and this knowledge is starting to be exploited for both molecular diagnostics and the development of novel strategies to combat cancer.

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Figure 1: The ubiquitin system offers several possibilities for therapeutic intervention.
Figure 2: Different strategies to target inhibitors of apopotosis (IAPs) in cancer.
Figure 3: Non-degradative ubiquitin modifications have a role in DNA repair.
Figure 4: Targeting the ubiquitin system in the nucleus.

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References

  1. Hershko, A. & Ciechanover, A. The ubiquitin system. Annu. Rev. Biochem. 67, 425–479 (1998).

    Article  CAS  PubMed  Google Scholar 

  2. Bennett, E. J. & Harper, J. W. DNA damage: ubiquitin marks the spot. Nature Struct. Mol. Biol. 15, 20–22 (2008).

    Article  CAS  Google Scholar 

  3. Katzmann, D. J., Odorizzi, G. & Emr, S. D. Receptor downregulation and multivesicular-body sorting. Nature Rev. Mol. Cell Biol. 3, 893–905 (2002).

    Article  CAS  Google Scholar 

  4. Haglund, K. & Dikic, I. Ubiquitylation and cell signaling. EMBO J. 24, 3353–3359 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Mukhopadhyay, D. & Riezman, H. Proteasome-independent functions of ubiquitin in endocytosis and signaling. Science 315, 201–205 (2007).

    Article  ADS  CAS  PubMed  Google Scholar 

  6. Pickart, C. M. Mechanisms underlying ubiquitination. Annu. Rev. Biochem. 70, 503–533 (2001).

    Article  CAS  PubMed  Google Scholar 

  7. Ikeda, F. & Dikic, I. Atypical ubiquitin chains: new molecular signals. EMBO Rep. 9, 536–542 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Hoeller, D., Hecker, C. M. & Dikic, I. Ubiquitin and ubiquitin-like proteins in cancer pathogenesis. Nature Rev. Cancer 6, 776–788 (2006).

    Article  CAS  Google Scholar 

  9. Bernassola, F., Karin, M., Ciechanover, A. & Melino, G. The HECT family of E3 ubiquitin ligases: multiple players in cancer development. Cancer Cell 14, 10–21 (2008).

    Article  CAS  PubMed  Google Scholar 

  10. Nakayama, K. I. & Nakayama, K. Ubiquitin ligases: cell-cycle control and cancer. Nature Rev. Cancer 6, 369–381 (2006).

    Article  CAS  Google Scholar 

  11. Bond, G. L., Hu, W. & Levine, A. J. MDM2 is a central node in the p53 pathway: 12 years and counting. Curr. Cancer Drug Targets 5, 3–8 (2005).

    Article  CAS  PubMed  Google Scholar 

  12. Vousden, K. H. & Prives, C. p53 and prognosis: new insights and further complexity. Cell 120, 7–10 (2005).

    CAS  PubMed  Google Scholar 

  13. Cardozo, T. & Pagano, M. Wrenches in the works: drug discovery targeting the SCF ubiquitin ligase and APC/C complexes. BMC Biochem. 8 (suppl. 1), S9 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Vassilev, L. T. MDM2 inhibitors for cancer therapy. Trends Mol. Med. 13, 23–31 (2007).

    Article  CAS  PubMed  Google Scholar 

  15. Guedat, P. & Colland, F. Patented small molecule inhibitors in the ubiquitin proteasome system. BMC Biochem. 8 (suppl. 1), S14 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Hjerpe, R. & Rodriguez, M. S. Alternative UPS drug targets upstream the 26S proteasome. Int. J. Biochem. Cell Biol. 40, 1126–1140 (2008).

    Article  CAS  PubMed  Google Scholar 

  17. Yang, Y. et al. Small molecule inhibitors of HDM2 ubiquitin ligase activity stabilize and activate p53 in cells. Cancer Cell 7, 547–559 (2005). This is the first report about the development of inhibitors that target the active site of a RING-type E3. The identified compound, HLI98, shows specificity for MDM2 and allows the activation of p53-dependent transcription in cells.

    Article  CAS  PubMed  Google Scholar 

  18. VanderBorght, A. et al. Effect of an hdm-2 antagonist peptide inhibitor on cell cycle progression in p53-deficient H1299 human lung carcinoma cells. Oncogene 25, 6672–6677 (2006).

    Article  CAS  PubMed  Google Scholar 

  19. Brooks, C. L. & Gu, W. p53 ubiquitination: Mdm2 and beyond. Mol. Cell 21, 307–315 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Issaeva, N. et al. Small molecule RITA binds to p53, blocks p53–HDM-2 interaction and activates p53 function in tumors. Nature Med. 10, 1321–1328 (2004). The authors identify RITA as a potent inhibitor of p53 degradation. RITA induced p53-dependent apoptosis in various tumour cells, and showed significant antitumour effects in vivo.

    Article  CAS  PubMed  Google Scholar 

  21. Frescas, D. & Pagano, M. Deregulated proteolysis by the F-box proteins SKP2 and β-TrCP: tipping the scales of cancer. Nature Rev. Cancer 8, 438–449 (2008).

    Article  CAS  Google Scholar 

  22. Hanahan, D. & Folkman, J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86, 353–364 (1996).

    Article  CAS  PubMed  Google Scholar 

  23. Kaelin, W. G. Jr . The von Hippel–Lindau tumor suppressor protein and clear cell renal carcinoma. Clin. Cancer Res. 13, 680S–684S (2007).

    Article  CAS  PubMed  Google Scholar 

  24. Srinivasula, S. M. & Ashwell, J. D. IAPs: what's in a name? Mol. Cell 30, 123–135 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Vaux, D. L. & Silke, J. IAPs, RINGs and ubiquitylation. Nature Rev. Mol. Cell Biol. 6, 287–297 (2005).

    Article  CAS  Google Scholar 

  26. Dierlamm, J. et al. The apoptosis inhibitor gene API2 and a novel 18q gene, MLT, are recurrently rearranged in the t(11;18)(q21;q21) associated with mucosa-associated lymphoid tissue lymphomas. Blood 93, 3601–3609 (1999).

    Article  CAS  PubMed  Google Scholar 

  27. Noels, H. et al. A novel TRAF6 binding site in MALT1 defines distinct mechanisms of NF-κB activation by API2–MALT1 fusions. J. Biol. Chem. 282, 10180–10189 (2007).

    Article  CAS  PubMed  Google Scholar 

  28. Wright, C. W. & Duckett, C. S. Reawakening the cellular death program in neoplasia through the therapeutic blockade of IAP function. J. Clin. Invest. 115, 2673–2678 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Varfolomeev, E. et al. c-IAP1 and c-IAP2 are critical mediators of TNFα-induced NF-κB activation. J. Biol. Chem. 283, 24295–24299 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Vince, J. E. et al. IAP antagonists target cIAP1 to induce TNFα-dependent apoptosis. Cell 131, 682–693 (2007). References 29 and 30 unravel the molecular mechanism of how SMAC mimetics kill cancer cells. Unexpectedly, this involves the induction of autoubiquitylation and degradation of IAPs leading to TNF-α-mediated cell death.

    Article  CAS  PubMed  Google Scholar 

  31. Cummings, J. et al. Method validation and preliminary qualification of pharmacodynamic biomarkers employed to evaluate the clinical efficacy of an antisense compound (AEG35156) targeted to the X-linked inhibitor of apoptosis protein XIAP. Br. J. Cancer 95, 42–48 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Nijman, S. M. et al. A genomic and functional inventory of deubiquitinating enzymes. Cell 123, 773–786 (2005).

    Article  CAS  PubMed  Google Scholar 

  33. Nijman, S. M. et al. The deubiquitinating enzyme USP1 regulates the Fanconi anemia pathway. Mol. Cell 17, 331–339 (2005).

    Article  CAS  PubMed  Google Scholar 

  34. Popov, N., Herold, S., Llamazares, M., Schulein, C. & Eilers, M. Fbw7 and Usp28 regulate Myc protein stability in response to DNA damage. Cell Cycle 6, 2327–2331 (2007).

    Article  CAS  PubMed  Google Scholar 

  35. Popov, N. et al. The ubiquitin-specific protease USP28 is required for MYC stability. Nature Cell Biol. 9, 765–774 (2007).

    Article  CAS  PubMed  Google Scholar 

  36. Stegmeier, F. et al. Anaphase initiation is regulated by antagonistic ubiquitination and deubiquitination activities. Nature 446, 876–881 (2007).

    Article  ADS  CAS  PubMed  Google Scholar 

  37. Wertz, I. E. et al. De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-κB signalling. Nature 430, 694–699 (2004). This paper describes the molecular mechanism of ubiquitin-chain editing by A20, a single molecule containing E3 ligase and deubiquitylating activities.

    Article  ADS  CAS  PubMed  Google Scholar 

  38. Sun, S. C. Deubiquitylation and regulation of the immune response. Nature Rev. Immunol. 8, 501–511 (2008).

    Article  CAS  Google Scholar 

  39. Massoumi, R., Chmielarska, K., Hennecke, K., Pfeifer, A. & Fassler, R. Cyld inhibits tumor cell proliferation by blocking Bcl-3-dependent NF-κB signaling. Cell 125, 665–677 (2006).

    Article  CAS  PubMed  Google Scholar 

  40. Liu, Y. et al. Discovery of inhibitors that elucidate the role of UCH-L1 activity in the H1299 lung cancer cell line. Chem. Biol. 10, 837–846 (2003).

    Article  CAS  PubMed  Google Scholar 

  41. Love, K. R., Catic, A., Schlieker, C. & Ploegh, H. L. Mechanisms, biology and inhibitors of deubiquitinating enzymes. Nature Chem. Biol. 3, 697–705 (2007).

    Article  CAS  Google Scholar 

  42. Rubin, D. M. & Finley, D. The proteasome: a protein-degrading organelle? Curr. Biol. 5, 854–858 (1995).

    Article  CAS  PubMed  Google Scholar 

  43. Dahlmann, B. Role of proteasomes in disease. BMC Biochem. 8 (suppl. 1), S3 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Karin, M. Nuclear factor-κB in cancer development and progression. Nature 441, 431–436 (2006).

    Article  ADS  CAS  PubMed  Google Scholar 

  45. Adams, J. The development of proteasome inhibitors as anticancer drugs. Cancer Cell 5, 417–421 (2004).

    Article  MathSciNet  CAS  PubMed  Google Scholar 

  46. Ling, Y. H. et al. Mechanisms of proteasome inhibitor PS-341-induced G2–M-phase arrest and apoptosis in human non-small cell lung cancer cell lines. Clin. Cancer Res. 9, 1145–1154 (2003).

    ADS  CAS  PubMed  Google Scholar 

  47. Meister, S. et al. Extensive immunoglobulin production sensitizes myeloma cells for proteasome inhibition. Cancer Res. 67, 1783–1792 (2007).

    Article  CAS  PubMed  Google Scholar 

  48. Gu, H., Chen, X., Gao, G. & Dong, H. Caspase-2 functions upstream of mitochondria in endoplasmic reticulum stress-induced apoptosis by bortezomib in human myeloma cells. Mol. Cancer Ther. 7, 2298–2307 (2008).

    Article  CAS  PubMed  Google Scholar 

  49. Tobinai, K. Proteasome inhibitor, bortezomib, for myeloma and lymphoma. Int. J. Clin. Oncol. 12, 318–326 (2007).

    Article  CAS  PubMed  Google Scholar 

  50. Dorsey, B. D. et al. Discovery of a potent, selective, and orally active proteasome inhibitor for the treatment of cancer. J. Med. Chem. 51, 1068–1072 (2008).

    Article  CAS  PubMed  Google Scholar 

  51. Piva, R. et al. CEP-18770: a novel, orally active proteasome inhibitor with a tumor-selective pharmacologic profile competitive with bortezomib. Blood 111, 2765–2775 (2008).

    Article  CAS  PubMed  Google Scholar 

  52. Nalepa, G., Rolfe, M. & Harper, J. W. Drug discovery in the ubiquitin–proteasome system. Nature Rev. Drug Discov. 5, 596–613 (2006).

    Article  CAS  Google Scholar 

  53. Miller, C. P. et al. NPI-0052, a novel proteasome inhibitor, induces caspase-8 and ROS-dependent apoptosis alone and in combination with HDAC inhibitors in leukemia cells. Blood 110, 267–277 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Chauhan, D. et al. Combination of proteasome inhibitors bortezomib and NPI-0052 trigger in vivo synergistic cytotoxicity in multiple myeloma. Blood 111, 1654–1664 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Richardson, P. G. et al. Bortezomib in the front-line treatment of multiple myeloma. Expert Rev. Anticancer Ther. 8, 1053–1072 (2008).

    Article  CAS  PubMed  Google Scholar 

  56. Nickeleit, I. et al. Argyrin A reveals a critical role for the tumor suppressor protein p27kip1 in mediating antitumor activities in response to proteasome inhibition. Cancer Cell 14, 23–35 (2008).

    Article  CAS  PubMed  Google Scholar 

  57. Hashizume, R. et al. The RING heterodimer BRCA1–BARD1 is a ubiquitin ligase inactivated by a breast cancer-derived mutation. J. Biol. Chem. 276, 14537–14540 (2001).

    Article  CAS  PubMed  Google Scholar 

  58. Brooks, C. L., Li, M. & Gu, W. Monoubiquitination: the signal for p53 nuclear export? Cell Cycle 3, 436–438 (2004).

    CAS  PubMed  Google Scholar 

  59. Nie, L., Sasaki, M. & Maki, C. G. Regulation of p53 nuclear export through sequential changes in conformation and ubiquitination. J. Biol. Chem. 282, 14616–14625 (2007).

    Article  CAS  PubMed  Google Scholar 

  60. Carter, S., Bischof, O., Dejean, A. & Vousden, K. H. C-terminal modifications regulate MDM2 dissociation and nuclear export of p53. Nature Cell Biol. 9, 428–435 (2007).

    Article  CAS  PubMed  Google Scholar 

  61. Moll, U. M., Wolff, S., Speidel, D. & Deppert, W. Transcription-independent pro-apoptotic functions of p53. Curr. Opin. Cell Biol. 17, 631–636 (2005).

    Article  CAS  PubMed  Google Scholar 

  62. Trotman, L. C. et al. Ubiquitination regulates PTEN nuclear import and tumor suppression. Cell 128, 141–156 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Wang, X. et al. NEDD4-1 is a proto-oncogenic ubiquitin ligase for PTEN. Cell 128, 129–139 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Cully, M., You, H., Levine, A. J. & Mak, T. W. Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis. Nature Rev. Cancer 6, 184–192 (2006).

    Article  CAS  Google Scholar 

  65. Gimm, O. et al. Differential nuclear and cytoplasmic expression of PTEN in normal thyroid tissue, and benign and malignant epithelial thyroid tumors. Am. J. Pathol. 156, 1693–1700 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Fouladkou, F. et al. The ubiquitin ligase Nedd4-1 is dispensable for the regulation of PTEN stability and localization. Proc. Natl Acad. Sci. USA 105, 8585–8590 (2008).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  67. Song, M. S. et al. The deubiquitinylation and localization of PTEN are regulated by a HAUSP–PML network. Nature 455, 813–817 (2008).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  68. Hurley, J. H., Lee, S. & Prag, G. Ubiquitin-binding domains. Biochem. J. 399, 361–372 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Bienko, M. et al. Ubiquitin-binding domains in Y-family polymerases regulate translesion synthesis. Science 310, 1821–1824 (2005).

    Article  ADS  CAS  PubMed  Google Scholar 

  70. Chen, Z. J. Ubiquitin signalling in the NF-κB pathway. Nature Cell Biol. 7, 758–765 (2005).

    Article  CAS  PubMed  Google Scholar 

  71. Verma, R. et al. Ubistatins inhibit proteasome-dependent degradation by binding the ubiquitin chain. Science 306, 117–120 (2004). Ubistatins are the first example of small molecules interfering with the recognition of specific ubiquitin chains by ubiquitin receptors.

    Article  ADS  CAS  PubMed  Google Scholar 

  72. Husnjak, K. et al. Proteasome subunit Rpn13 is a novel ubiquitin receptor. Nature 453, 481–488 (2008). This paper shows that Rpn13 is a second proteasomal ubiquitin receptor that links the recognition of ubiquitylated proteins with the disassembly of ubiquitin chains by Uch37.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  73. Tatham, M. H. et al. Unique binding interactions among Ubc9, SUMO and RanBP2 reveal a mechanism for SUMO paralog selection. Nature Struct. Mol. Biol. 12, 67–74 (2005).

    Article  CAS  Google Scholar 

  74. Tatham, M. H. et al. RNF4 is a poly-SUMO-specific E3 ubiquitin ligase required for arsenic-induced PML degradation. Nature Cell Biol. 10, 538–546 (2008).

    Article  CAS  PubMed  Google Scholar 

  75. Lallemand-Breitenbach, V. et al. Arsenic degrades PML or PML-RARα through a SUMO-triggered RNF4/ubiquitin-mediated pathway. Nature Cell Biol. 10, 547–555 (2008). References 74 and 75 describe the SUMO-dependent ubiquitylation of a protein and explains how arsenic-induced SUMOylation leads to degradation of the PML–RAR-α oncogene.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank A. Ciechanover, R. Deshaies, M. Pagano, K. Rajalingam, D. Vucic and members of the Dikic laboratory for critical reading of the manuscript. We apologize to those investigators whose contributions are not described here because of space limitations. D.H. is supported by a European Molecular Biology Organization (EMBO) long-term fellowship. I.D. acknowledges support from the German Research Foundation (DFG) and the Cluster of Excellence 'Macromolecular Complexes' (Goethe University Frankfurt).

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Authors and Affiliations

  1. Division of Medical Biochemistry, Innsbruck Medical University, Biocenter, Fritz-Pregl-Strasse 3, Innsbruck, 6020, Austria

    Daniela Hoeller

  2. Institute of Biochemistry II and Cluster of Excellence 'Macromolecular Complexes', Goethe University, Theodor-Stern-Kai 7, Frankfurt, 60590, Germany

    Ivan Dikic

  3. Tumor Biology Program, Mediterranean Institute for Life Sciences, Split, 21000, Croatia

    Ivan Dikic

  4. Department of Immunology, School of Medicine, University of Split, Soltanska 2, Split, 21000, Croatia

    Ivan Dikic

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Correspondence should be addressed to I.D (dikic@biochem2.uni-frankfurt.de).

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Hoeller, D., Dikic, I. Targeting the ubiquitin system in cancer therapy. Nature 458, 438–444 (2009). https://doi.org/10.1038/nature07960

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