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.

  • Original Article
  • Published:

Androgen induces G3BP2 and SUMO-mediated p53 nuclear export in prostate cancer

Oncogene volume 36, pages 6272–6281 (2017)Cite this article

Subjects

Abstract

The androgen receptor (AR) has a central role in prostate cancer progression, particularly treatment-resistance disease including castration-resistant prostate cancer. Loss of the p53 tumor suppressor, a nuclear transcription factor, is also known to contribute to prostate malignancy. Here we report that p53 is translocated to the cytoplasm by androgen-mediated induction of G3BP2, a newly described direct target gene of AR. G3BP2 induces both cell cycle progression and blocks apoptosis. Translocation of p53 is regulated by androgen-dependent sumoylation mediated by the G3BP2-interacting SUMO-E3 ligase, RanBP2. G3BP2 knockdown results in reduced tumor growth and increased nuclear p53 accumulation in mouse xenograft models of prostate cancer with or without long-term androgen deprivation. Moreover, strong cytoplasmic p53 localization is correlated clinically with elevated G3BP2 expression and predicts poor prognosis and disease progression to the hormone-refractory state. Our findings reveal a new AR-mediated mechanism of p53 inhibition that promotes treatment-resistant prostate cancer.

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
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Dehm SM, Tindall DJ . Molecular regulation of androgen action in prostate cancer. J Cell Biochem 2006; 99: 333–344.

    Article  CAS  PubMed  Google Scholar 

  2. Debes JD, Tindall DJ . The role of androgens and the androgen receptor in prostate cancer. Cancer Lett 2002; 187: 1–7.

    Article  CAS  PubMed  Google Scholar 

  3. Wang Q, Li W, Liu XS, Carroll JS, Jänne OA, Keeton EK et al. A hierarchical network of transcription factors governs androgen receptor-dependent prostate cancer growth. Mol Cell 2007; 27: 380–392.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Chen CD, Welsbie DS, Tran C, Baek SH, Chen R, Vessella R et al. Molecular determinants of resistance to antiandrogen therapy. Nat Med 2004; 10: 33–39.

    Article  PubMed  Google Scholar 

  5. Feldman BJ, Feldman D . The development of androgen-independent prostate cancer. Nat Rev Cancer 2001; 1: 34–45.

    Article  CAS  PubMed  Google Scholar 

  6. Wang Q, Li W, Zhang Y, Yuan X, Xu K, Yu J et al. Androgen receptor regulates a distinct transcription program in androgen-independent prostate cancer. Cell 2009; 138: 245–256.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Takayama K, Inoue S . Transcriptional network of androgen receptor in prostate cancer progression. Int J Urol 2013; 20: 756–768.

    Article  CAS  PubMed  Google Scholar 

  8. Meek DW . Tumour suppression by p53: a role for the DNA damage response? Nat Rev Cancer 2009; 9: 714–723.

    Article  CAS  PubMed  Google Scholar 

  9. Riley T, Sontag E, Chen P, Levine A . Transcriptional control of human p53-regulated genes. Nat Rev Mol Cell Biol 2008; 9: 402–412.

    Article  CAS  PubMed  Google Scholar 

  10. Vogelstein B, Lane D, Levine AJ . Surfing the p53 network. Nature 2000; 408: 307–310.

    Article  CAS  PubMed  Google Scholar 

  11. Chen Z, Trotman LC, Shaffer D, Lin HK, Dotan ZA, Niki M et al. Cruicial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature 2005; 436: 725–730.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kruse JP, Gu W . Modes of p53 regulation. Cell 2009; 137: 609–622.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Jenkins LM, Durell SR, Mazur SJ, Appella E . p53 N-terminal phosphorylation: a defining layer of complex regulation. Carcinogenesis 2012; 33: 1441–1449.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Brooks CL, Gu W . The impact of acetylation and deacetylation on the p53 pathway. Protein Cell 2011; 2: 456–462.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Li M, Brooks CL, Wu-Baer F, Chen D, Baer R, Gu W . Mono-versus polyubiquitination: differential control of p53 fate by Mdm2. Science 2003; 302: 1972–1975.

    Article  CAS  PubMed  Google Scholar 

  16. Rodriguez MS, Desterro JM, Lain S, Midgley CA, Lane DP, Hay RT . SUMO-1 modification activates the transcriptional response of p53. EMBO J 1999; 18: 6455–6461.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Schmidt D, Muller S . Members of the PIAS family act as SUMO ligase for c-jun and p53 and repress p53 activity. Proc Natl Acad Sci USA 2002; 99: 2872–2877.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Carter S, Bischof O, Dejean A, Vousden KH . C-terminal modifications regulate MDM2 dissociation and nuclear export of p53. Nat Cell Biol 2007; 9: 428–435.

    Article  CAS  PubMed  Google Scholar 

  19. Santiago A, Li D, Zhao LY, Godsey A, Liao D . p53 SUMOylation promotes its nuclear export by facilitating its release from the nuclear export receptor CRM1. Mol Biol Cell 2013; 24: 2739–2752.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Gostissa M, Hengstermann A, Fogal V, Sandy P, Schwartz SE, Scheffner M et al. Activation of p53 by conjugation to the ubiquitin-like protein SUMO-1. EMBO J 18: 6462–6471.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kahyo T, Nishida T, Yasuda H . Involvement of PIAS1 in the sumoylation of tumor suppressor p53. Mol Cell 2001; 8: 713–718.

    Article  CAS  PubMed  Google Scholar 

  22. Takayama K, Horie-Inoue K, Katayama S, Suzuki T, Tsutsumi S, Ikeda K et al. Androgen-responsive long noncoding RNA CTBP1-AS promotes prostate cancer. EMBO J 2013; 32: 1665–1680.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Stattin P, Bergh A, Karlberg L, Nordgren H, Damber JE . p53 immunoreactivity as prognostic marker for cancer-specific survival in prostate cancer. Eur Urol 1996; 30: 65–72.

    Article  CAS  PubMed  Google Scholar 

  24. Kluth M, Harasimowicz S, Burkhardt L, Grupp K, Krohn A, Prien K et al. Clinical significance of different types of p53 gene alteration in surgically treated prostate cancer. Int J Cancer 2014; 135: 1369–1380.

    Article  CAS  PubMed  Google Scholar 

  25. Quinn DI, Henshall SM, Head DR, Golovsky D, Wilson JD, Brenner PC et al. Prognostic significance of p53 nuclear accumulation in localized prostate cancer treated with radical prostatectomy. Cancer Res 2000; 60: 1585–1594.

    CAS  PubMed  Google Scholar 

  26. Takayama K, Tsutsumi S, Katayama S, Okayama T, Horie-Inoue K, Ikeda K et al. Integration of cap analysis of gene expression and chromatin IP analysis on array reveals genome-wide androgen receptor signaling in prostate cancer cells. Oncogene 2011; 30: 619–630.

    Article  CAS  PubMed  Google Scholar 

  27. Takayama K, Suzuki T, Fujimura T, Urano T, Takahashi S, Homma Y et al. CtBP2 modulates the androgen receptor to promote prostate cancer progression. Cancer Res 2014; 74: 6542–6553.

    Article  CAS  PubMed  Google Scholar 

  28. Huang DW, Sherman BT, Lempicki RA . Systematic and integrative analysis of large gene lists using DAVID Bioinformatics Resources. Nat Protoc 2009; 4: 44–57.

    Article  CAS  Google Scholar 

  29. Irvine K, Stirling R, Hume D, Kennedy D . Rasputin, more promiscuous than ever: a review of G3BP. Int J Dev Biol 2004; 48: 1065–1077.

    Article  CAS  PubMed  Google Scholar 

  30. French J, Stirling R, Walsh M, Kennedy HD . The expression of Ras-GTPase activating protein SH3 domain-binding proteins, G3BPs, in human breast cancers. Histochem J 2002; 34: 223–231.

    Article  CAS  PubMed  Google Scholar 

  31. Guitard E, Parker F, Millon R, Abecassis J, Tocque B . G3BP is overexpressed in human tumors and promotes S phase entry. Cancer Lett 2001; 162: 213–221.

    Article  CAS  PubMed  Google Scholar 

  32. Kim MM, Wiederschain D, Kennedy D, Hansen E, Yuan ZM . Modulation of p53 and MDM2 activity by novel interaction with Ras-GAP binding proteins (G3BP). Oncogene 2007; 26: 4209–4215.

    Article  CAS  PubMed  Google Scholar 

  33. Wang Q, Carroll JS, Brown M . Spatial and temporal recruitment of androgen receptor and its coactivators involves chromosomal looping and polymerase tracking. Mol Cell 2005; 19: 631–642.

    Article  CAS  PubMed  Google Scholar 

  34. Misawa A, Takayama K, Urano T, Inoue S . Androgen-induced long noncoding RNA (lncRNA) SOCS2-AS1 promotes cell growth and inhibits apoptosis in prostate cancer cells. J Biol Chem 2016; 291: 17861–17880.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Güttler T, Görlich D . Ran-dependent nuclear export mediators: a structural perspective. EMBO J 2011; 30: 3457–3474.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Werner A, Flotho A, Melchior F . The RanBP2/RanGAP1*SUMO1/Ubc9 complex is a multisubunit SUMO E3 ligase. Mol Cell 2012; 46: 287–298.

    Article  CAS  PubMed  Google Scholar 

  37. Liu C, Zhu Y, Lou W, Nadiminty N, Chen X, Zhou Q et al. Functional p53 determines docetaxel sensitivity in prostate cancer cells. Prostate 2013; 73: 418–427.

    Article  CAS  PubMed  Google Scholar 

  38. Moretti RM, Montagnani Marelli M, Taylor DM, Martini PG, Marzagalli M, Limonta P et al. Gonadotropin-releasing hormone agonists sensitize, and resensitize, prostate cancer cells to docetaxel in a p53-dependent manner. PLoS One 2014; 9: e93713.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Chappell WH, Lehmann BD, Terrian DM, Abrams SL, Steelman LS, McCubrey JA et al. p53 expression controls prostate cancer sensitivity to chemotherapy and the MDM2 inhibitor Nutlin-3. Cell Cycle 2012; 11: 4579–4588.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Parker F, Maurier F, Delumeau I, Duchesne M, Faucher D, Debussche L et al. A Ras-GTPase-activating protein SH3-domain-binding protein. Mol Cell Biol 1996; 16: 2561–2569.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Winslow S, Leandersson K, Larsson C . Regulation of PMP22 mRNA by G3BP1 affects cell proliferation in breast cancer cells. Mol Cancer 2013; 12: 156.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Tourrière H, Chebli K, Zekri L, Courselaud B, Blanchard JM, Bertrand E et al. The RasGAP-associated endoribonuclease G3BP assembles stress granules. J Cell Biol 2003; 160: 823–831.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Ohtsubo C, Shiokawa D, Kodama M, Gaiddon C, Nakagama H, Jochemsen AG et al. Cytosolic tethering is involved in synergistic inhibition of p53 by Mdmx and Mdm2. Cancer Sci 2009; 100: 1291–1299.

    Article  CAS  PubMed  Google Scholar 

  44. Muller PA, Vousden KH . Mutant p53 in cancer: new functions and therapeutic opportunities. Cancer Cell 2014; 25: 304–317.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Grasso CS, Wu YM, Robinson DR, Cao X, Dhanasekaran SM, Khan AP et al. The mutational landscape of lethal castration-resistant prostate cancer. Nature 2012; 487: 239–243.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Lu X, Liu DP, Xu Y . The gain of function of p53 cancer mutant in promoting mammary tumorigenesis. Oncogene 2013; 32: 2900–2906.

    Article  CAS  PubMed  Google Scholar 

  47. Obinata D, Takayama K, Murata T, Kumagai J, Fujimura T, Takahashi S et al. Oct1 regulates cell growth of LNCaP cells and is a prognostic factor for prostate cancer. Int J Cancer 2012; 130: 1021–1028.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Professor Takashi Suzuki (Tohoku University) for comments on our pathological analysis. We thank E Sakamoto and N Sasaki for technical assistance. This work was supported by Grants of the Cell Innovation Program and the P-Direct (both to SI) from the MEXT, Japan; by Grants (to SI and KT) from the JSPS, Japan; by Grants-in-Aid (to SI) from the MHLW, Japan; by the Program for Promotion of Fundamental Studies in Health Sciences (to SI), NIBIO, Japan; by Grants from Takeda Science Foundation (to SI and KT); and by Grants from Mochida Memorial Research Foundation (to KT), Japan, the Yasuda Memorial Foundation (to KT) and Princess Takamatsu Cancer Research Fund (to KT).

Author contributions

KT designed the study, analyzed genome-wide androgen signaling and performed the animal experiments. DA and KT performed the cell-based experiments and analyzed data. DA, DO and ST performed immunohistochemistry. YS performed RNA-seq. TT performed mass spectrometry and supervised the study. SI designed and supervised the study. TU and TF discussed the data. DA, KT, TT and SI wrote the manuscript.

Author information

Author notes

  1. D Ashikari, K Takayama and T Tanaka: These authors are co-first authors.

Authors and Affiliations

  1. Department of Anti-Aging Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

    D Ashikari, K Takayama, D Obinata, T Urano & S Inoue

  2. Department of Urology, Nihon University School of Medicine, Tokyo, Japan

    D Ashikari, D Obinata & S Takahashi

  3. Department of Functional Biogerontology, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan

    K Takayama, D Obinata & S Inoue

  4. Department of Clinical Cell Biology and Division of Endocrinology and Metabolism, Graduate School of Medicine, Chiba University, Chiba, Japan

    T Tanaka

  5. Department of Medical Genome Sciences, Laboratory of Functional Genomics, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan

    Y Suzuki

  6. Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

    T Fujimura

  7. Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Hidaka, Japan

    S Inoue

Authors
  1. D Ashikari
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. K Takayama
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. T Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Y Suzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. D Obinata
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. T Fujimura
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. T Urano
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. S Takahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. S Inoue
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S Inoue.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ashikari, D., Takayama, K., Tanaka, T. et al. Androgen induces G3BP2 and SUMO-mediated p53 nuclear export in prostate cancer. Oncogene 36, 6272–6281 (2017). https://doi.org/10.1038/onc.2017.225

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2017.225

This article is cited by

Search

Advanced search

Quick links