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.

  • Article
  • Published:

An oncogene–tumor suppressor cascade drives metastatic prostate cancer by coordinately activating Ras and nuclear factor-κB

Nature Medicine volume 16, pages 286–294 (2010)Cite this article

Subjects

An Author Correction to this article was published on 21 February 2024

This article has been updated

Abstract

Metastasis is responsible for the majority of prostate cancer–related deaths; however, little is known about the molecular mechanisms that underlie this process. Here we identify an oncogene–tumor suppressor cascade that promotes prostate cancer growth and metastasis by coordinately activating the small GTPase Ras and nuclear factor-κB (NF-κB). Specifically, we show that loss of the Ras GTPase-activating protein (RasGAP) gene DAB2IP induces metastatic prostate cancer in an orthotopic mouse tumor model. Notably, DAB2IP functions as a signaling scaffold that coordinately regulates Ras and NF-κB through distinct domains to promote tumor growth and metastasis, respectively. DAB2IP is suppressed in human prostate cancer, where its expression inversely correlates with tumor grade and predicts prognosis. Moreover, we report that epigenetic silencing of DAB2IP is a key mechanism by which the polycomb-group protein histone-lysine N-methyltransferase EZH2 activates Ras and NF-κB and triggers metastasis. These studies define the mechanism by which two major pathways can be simultaneously activated in metastatic prostate cancer and establish EZH2 as a driver of metastasis.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: DAB2IP suppression induces prostate tumor development.
Figure 2: DAB2IP loss, but not H-RasV12 expression, promotes invasion and widespread metastasis.
Figure 3: The RasGAP activity of DAB2IP underlies some but not all of its tumor and metastasis suppressor function.
Figure 4: DAB2IP loss promotes tumorigenesis and metastasis via concomitant effects on Ras and NF-κB.
Figure 5: EZH2 promotes tumorigenesis and metastasis via suppression of DAB2IP.
Figure 6: DAB2IP is suppressed in human prostate cancer.

Similar content being viewed by others

Change history

References

  1. Nelson, W.G., De Marzo, A.M. & Isaacs, W.B. Prostate cancer. N. Engl. J. Med. 349, 366–381 (2003).

    Article  CAS  PubMed  Google Scholar 

  2. Jemal, A. et al. Cancer statistics, 2008. CA Cancer J. Clin. 58, 71–96 (2008).

    Article  PubMed  Google Scholar 

  3. Jeong, J.H. et al. BRAF activation initiates but does not maintain invasive prostate adenocarcinoma. PLoS One 3, e3949 (2008).

    Article  ADS  PubMed  PubMed Central  Google Scholar 

  4. Shen, M.M. & Abate-Shen, C. Pten inactivation and the emergence of androgen-independent prostate cancer. Cancer Res. 67, 6535–6538 (2007).

    Article  CAS  PubMed  Google Scholar 

  5. Gioeli, D., Mandell, J.W., Petroni, G.R., Frierson, H.F. Jr. & Weber, M.J. Activation of mitogen-activated protein kinase associated with prostate cancer progression. Cancer Res. 59, 279–284 (1999).

    CAS  PubMed  Google Scholar 

  6. Malik, S.N. et al. Immunohistochemical demonstration of phospho-Akt in high Gleason grade prostate cancer. Clin. Cancer Res. 8, 1168–1171 (2002).

    ADS  PubMed  Google Scholar 

  7. Carter, B.S., Epstein, J.I. & Isaacs, W.B. ras gene mutations in human prostate cancer. Cancer Res. 50, 6830–6832 (1990).

    CAS  PubMed  Google Scholar 

  8. Gumerlock, P.H., Poonamallee, U.R., Meyers, F.J. & deVere White, R.W. Activated ras alleles in human carcinoma of the prostate are rare. Cancer Res. 51, 1632–1637 (1991).

    CAS  PubMed  Google Scholar 

  9. Cho, N.Y. et al. BRAF and KRAS mutations in prostatic adenocarcinoma. Int. J. Cancer 119, 1858–1862 (2006).

    Article  CAS  PubMed  Google Scholar 

  10. Bernards, A. & Settleman, J. GEFs in growth factor signaling. Growth Factors 25, 355–361 (2007).

    Article  CAS  PubMed  Google Scholar 

  11. Bernards, A. & Settleman, J. GAPs in growth factor signaling. Growth Factors 23, 143–149 (2005).

    Article  CAS  PubMed  Google Scholar 

  12. Riccardi, V.M. Neurofibromatosis: Phenotype, Natural History and Pathogenesis. Ch. 3 (The Johns Hopkins University Press, Baltimore, 1992).

    Google Scholar 

  13. Ding, L. et al. Somatic mutations affect key pathways in lung adenocarcinoma. Nature 455, 1069–1075 (2008).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  14. Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455, 1061–1068 (2008).

  15. McGillicuddy, L.T. et al. Proteasomal and genetic inactivation of the NF1 tumor suppressor in gliomagenesis. Cancer Cell 16, 44–54 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Johannessen, C.M. et al. The NF1 tumor suppressor critically regulates TSC2 and mTOR. Proc. Natl. Acad. Sci. USA 102, 8573–8578 (2005).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  17. von Bergh, A.R. et al. Identification of a novel RAS GTPase–activating protein (RASGAP) gene at 9q34 as an MLL fusion partner in a patient with de novo acute myeloid leukemia. Genes Chromosom. Cancer 39, 324–334 (2004).

    Article  CAS  PubMed  Google Scholar 

  18. Dote, H. et al. Aberrant promoter methylation in human DAB2 interactive protein (hDAB2IP) gene in breast cancer. Clin. Cancer Res. 10, 2082–2089 (2004).

    Article  CAS  PubMed  Google Scholar 

  19. Dote, H. et al. Aberrant promoter methylation in human DAB2 interactive protein (hDAB2IP) gene in gastrointestinal tumour. Br. J. Cancer 92, 1117–1125 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Yano, M. et al. Aberrant promoter methylation of human DAB2 interactive protein (hDAB2IP) gene in lung cancers. Int. J. Cancer 113, 59–66 (2005).

    Article  CAS  PubMed  Google Scholar 

  21. Chen, H., Tu, S.W. & Hsieh, J.T. Down-regulation of human DAB2IP gene expression mediated by polycomb Ezh2 complex and histone deacetylase in prostate cancer. J. Biol. Chem. 280, 22437–22444 (2005).

    Article  CAS  PubMed  Google Scholar 

  22. Ke, X.S. et al. Genome-wide profiling of histone h3 lysine 4 and lysine 27 trimethylation reveals an epigenetic signature in prostate carcinogenesis. PLoS One 4, e4687 (2009).

    Article  ADS  PubMed  PubMed Central  Google Scholar 

  23. Berger, R. et al. Androgen-induced differentiation and tumorigenicity of human prostate epithelial cells. Cancer Res. 64, 8867–8875 (2004).

    Article  CAS  PubMed  Google Scholar 

  24. Arai, Y. et al. Radical prostatectomy for clinically localized prostate cancer: local tumor extension and prognosis. Int. J. Urol. 3, 373–378 (1996).

    Article  CAS  PubMed  Google Scholar 

  25. Sørensen, H.T., Mellemkjaer, L., Olsen, J.H. & Baron, J.A. Prognosis of cancers associated with venous thromboembolism. N. Engl. J. Med. 343, 1846–1850 (2000).

    Article  PubMed  Google Scholar 

  26. Scheel, C., Onder, T., Karnoub, A. & Weinberg, R.A. Adaptation versus selection: the origins of metastatic behavior. Cancer Res. 67, 11476–11479, discussion 11479–11480 (2007).

    Article  CAS  PubMed  Google Scholar 

  27. Thiery, J.P. Epithelial-mesenchymal transitions in tumour progression. Nat. Rev. Cancer 2, 442–454 (2002).

    Article  CAS  PubMed  Google Scholar 

  28. Weinberg, R.A. The Biology of Cancer. (Garland Science, New York, 2007).

    Google Scholar 

  29. Yang, J. et al. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 117, 927–939 (2004).

    Article  CAS  PubMed  Google Scholar 

  30. Joyce, J.A. & Pollard, J.W. Microenvironmental regulation of metastasis. Nat. Rev. Cancer 9, 239–252 (2009).

    Article  CAS  PubMed  Google Scholar 

  31. Zhang, H. et al. AIP1/DAB2IP, a novel member of the Ras-GAP family, transduces TRAF2-induced ASK1-JNK activation. J. Biol. Chem. 279, 44955–44965 (2004).

    Article  CAS  PubMed  Google Scholar 

  32. Huber, M.A., Beug, H. & Wirth, T. Epithelial-mesenchymal transition: NF-κB takes center stage. Cell Cycle 3, 1477–1480 (2004).

    Article  CAS  PubMed  Google Scholar 

  33. Naugler, W.E. & Karin, M. NF-κB and cancer-identifying targets and mechanisms. Curr. Opin. Genet. Dev. 18, 19–26 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Hayden, M.S. & Ghosh, S. Shared principles in NF-κB signaling. Cell 132, 344–362 (2008).

    Article  CAS  PubMed  Google Scholar 

  35. Mayo, M.W. et al. Requirement of NF-κB activation to suppress p53-independent apoptosis induced by oncogenic Ras. Science 278, 1812–1815 (1997).

    Article  ADS  CAS  PubMed  Google Scholar 

  36. Simon, J.A. & Lange, C.A. Roles of the EZH2 histone methyltransferase in cancer epigenetics. Mutat. Res. 647, 21–29 (2008).

    Article  CAS  PubMed  Google Scholar 

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

    Article  ADS  CAS  PubMed  Google Scholar 

  38. Yu, J. et al. A polycomb repression signature in metastatic prostate cancer predicts cancer outcome. Cancer Res. 67, 10657–10663 (2007).

    Article  CAS  PubMed  Google Scholar 

  39. Kondo, Y. et al. Gene silencing in cancer by histone H3 lysine 27 trimethylation independent of promoter DNA methylation. Nat. Genet. 40, 741–750 (2008).

    Article  CAS  PubMed  Google Scholar 

  40. Vanaja, D.K., Cheville, J.C., Iturria, S.J. & Young, C.Y. Transcriptional silencing of zinc finger protein 185 identified by expression profiling is associated with prostate cancer progression. Cancer Res. 63, 3877–3882 (2003).

    CAS  PubMed  Google Scholar 

  41. Lapointe, J. et al. Gene expression profiling identifies clinically relevant subtypes of prostate cancer. Proc. Natl. Acad. Sci. USA 101, 811–816 (2004).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  42. Tomlins, S.A., Rubin, M.A. & Chinnaiyan, A.M. Integrative biology of prostate cancer progression. Annu. Rev. Pathol. 1, 243–271 (2006).

    Article  CAS  PubMed  Google Scholar 

  43. Luo, J.H. et al. Gene expression analysis of prostate cancers. Mol. Carcinog. 33, 25–35 (2002).

    Article  CAS  PubMed  Google Scholar 

  44. Daskivich, T.J. & Oh, W.K. Recent progress in hormonal therapy for advanced prostate cancer. Curr. Opin. Urol. 16, 173–178 (2006).

    Article  PubMed  Google Scholar 

  45. Abate-Shen, C. & Shen, M.M. Mouse models of prostate carcinogenesis. Trends Genet. 18, S1–S5 (2002).

    Article  CAS  PubMed  Google Scholar 

  46. Wang, S. et al. Prostate-specific deletion of the murine Pten tumor suppressor gene leads to metastatic prostate cancer. Cancer Cell 4, 209–221 (2003).

    Article  CAS  PubMed  Google Scholar 

  47. Henry, D.O. et al. Ral GTPases contribute to regulation of cyclin D1 through activation of NF-kappaB. Mol. Cell. Biol. 20, 8084–8092 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Barbie, D.A. et al. Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1. Nature 462, 108–112 (2009).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  49. Sellers, W.R. & Loda, M. The EZH2 polycomb transcriptional repressor—a marker or mover of metastatic prostate cancer? Cancer Cell 2, 349–350 (2002).

    Article  CAS  PubMed  Google Scholar 

  50. Chen, H., Toyooka, S., Gazdar, A.F. & Hsieh, J.T. Epigenetic regulation of a novel tumor suppressor gene (hDAB2IP) in prostate cancer cell lines. J. Biol. Chem. 278, 3121–3130 (2003).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The PMMP-luc-neo retroviral luciferase construct was generously provided by A.L. Kung and M. Chheda (Dana-Farber Cancer Institute (DFCI)). pRL-TK was a gift from J. Boehm (Broad Institute). We thank D. Barbie (DFCI), J. Boehm for NF-κB target primers and R. Chen (DFCI) for IκBαSR and G. Evan for helpful discussions. This grant was supported by in part by the US Department of Defense (PC074048) and the Ludwig Center at Dana-Farber/Harvard Cancer Center.

Author information

Authors and Affiliations

  1. Genetics Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA

    Junxia Min, Sara K McLaughlin, Elizabeth E Reczek, Thomas De Raedt & Karen Cichowski

  2. Harvard Medical School, Boston, Massachusetts, USA

    Junxia Min, Giuseppe Fedele, Sara K McLaughlin, Elizabeth E Reczek, Thomas De Raedt, Isil Guney, David E Strochlic, Rameen Beroukhim, Roderick T Bronson, William C Hahn, Massimo Loda & Karen Cichowski

  3. Department of Cancer Biology, Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA

    Alexander Zaslavsky & Sandra Ryeom

  4. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

    Giuseppe Fedele, Isil Guney, David E Strochlic, Rameen Beroukhim, William C Hahn & Massimo Loda

  5. Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

    Laura E MacConaill & William C Hahn

  6. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

    Rameen Beroukhim

  7. Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA

    Rameen Beroukhim, William C Hahn & Massimo Loda

  8. Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA

    Massimo Loda

  9. Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

    Massimo Loda

  10. Ludwig Center at Dana-Farber/Harvard Cancer Center, Boston, Massachusetts, USA

    Karen Cichowski

Authors
  1. Junxia Min
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alexander Zaslavsky
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Giuseppe Fedele
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sara K McLaughlin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Elizabeth E Reczek
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Thomas De Raedt
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Isil Guney
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. David E Strochlic
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Laura E MacConaill
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Rameen Beroukhim
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Roderick T Bronson
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Sandra Ryeom
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. William C Hahn
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Massimo Loda
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Karen Cichowski
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

J.M., A.Z., S.K.M., E.E.R., I.G. and D.E.S. performed in vitro and in vivo experiments. G.F., R.T.B. and M.L. analyzed and interpreted the immunohistochemistry and histology experiments. G.F. performed analysis on tissue microarrays. T.D.R. performed statistical analysis. L.E.M. and R.B. performed Sequenome analysis. S.R., W.C.H. and M.L. provided scientific advice and helpful comments on manuscript. J.M. and K.C. conceptualized experiments, prepared figures and drafted the manuscript.

Corresponding author

Correspondence to Karen Cichowski.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figure 1–10 and Supplementary Table 1 (PDF 971 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Min, J., Zaslavsky, A., Fedele, G. et al. An oncogene–tumor suppressor cascade drives metastatic prostate cancer by coordinately activating Ras and nuclear factor-κB. Nat Med 16, 286–294 (2010). https://doi.org/10.1038/nm.2100

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.2100

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer