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Basic Research

Transcription alterations of members of the ubiquitin–proteasome network in prostate carcinoma

Prostate Cancer and Prostatic Diseases volume 14, pages 38–45 (2011)Cite this article

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Abstract

The purpose of this work was to investigate the role of the ubiquitin–proteasome network (UPN) in prostate cancer (PCA) and to elicit potential markers for this disease. The UPN represents a key factor in the maintenance of cellular homoeostasis as a result of its fundamental function in the regulation of intracellular protein degradation. Members of this network have a role in the biology of haematological and solid tumours. Tumour cells and normal epithelial cells from 22 prostatectomy specimens were isolated by laser microdissection. Prostate biopsy samples from healthy individuals served for technical calibration and as controls. Transcript levels of eight selected genes with E3 ubiquitin ligase activity (labelling target proteins for proteasome degradation) and two genes belonging to the proteasome–multienzyme complex itself were analysed by quantitative real-time RT-PCR. The proteasome genes PSMC4 and PSMB5 and the E3 ubiquitin ligase NEDD4L were significantly and coherently upregulated in PCA cells compared with the corresponding adjacent normal prostate tissue. Transcription of the E3 ubiquitin ligase SMURF2 was significantly higher in organ-confined tumours (pT2) compared with non-organ-confined cancers (pT3). The results indicate a role for PSMC4 and PSMB5 and the E3 ubiquitin ligase NEDD4L in prostate tumourigenesis, whereas SMURF2 downregulation could be associated with clinical progression. NEDD4L and SMURF2 both target transforming growth factor (TGF)-β for degradation. This reflects the pleiotropic role of the TGF-β signalling pathway acting as a tumour suppressor in normal and pre-cancerous cells, but having oncogenic properties in progressing cancer. Further studies have to elucidate whether these alterations could represent clinically relevant PCA-diagnostic and progression markers.

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References

  1. Schwab M . Ubiquitin. In: Schwab M, (eds). Encyclopedic Reference of Cancer. Berlin, Heidelberg, New York: Springer, 2001. p 937–943.

    Chapter  Google Scholar 

  2. Zwickl P, Baumeister W . The Proteasome-Ubiquitin Protein Degradation Pathway. Berlin, Heidelberg, New York: Springer, 2002.

    Book  Google Scholar 

  3. Cooper GM . Protein degradation. In: ASM Press Washington DC, (eds). The Cell, A Molecular Approach, 2. ed. Sunderland Massechusetts: Sinauer Associates Inc, 2000; p. 305–309.

    Google Scholar 

  4. Mani A, Gelmann EP . The ubiquitin-proteasome pathway and its role in cancer. J Clin Oncol 2005; 23: 4776–4789.

    Article  CAS  PubMed  Google Scholar 

  5. Burger AM, Seth AK . The ubiquitin-mediated protein degradation pathway in cancer: therapeutic implications. Eur J Cancer 2004; 40: 2217–2229.

    Article  CAS  PubMed  Google Scholar 

  6. Devoy A, Soane T, Welchman R, Mayer RJ . The ubiquitin-proteasome system and cancer. Essays Biochem 2005; 41: 187–203.

    Article  CAS  PubMed  Google Scholar 

  7. Hellwinkel OJ, Rogmann JP, Asong LE, Luebke AM, Eichelberg C, Ahyai S et al. A comprehensive analysis of transcript signatures of the phosphatidylinositol-3 kinase/protein kinase B signal-transduction pathway in prostate cancer. BJU Int 2008; 101: 1454–1460.

    Article  CAS  PubMed  Google Scholar 

  8. Schlomm T, Luebke AM, Sultmann H, Hellwinkel OJ, Sauer U, Poustka A et al. Extraction and processing of high quality RNA from impalpable and macroscopically invisible prostate cancer for microarray gene expression analysis. Int J Oncol 2005; 27: 713–720.

    CAS  PubMed  Google Scholar 

  9. Hanahan D, Weinberg RA . The hallmarks of cancer. Cell 2000; 100: 57–70.

    Article  CAS  PubMed  Google Scholar 

  10. Hershko A, Ciechanover A . The ubiquitin system. Annu Rev Biochem 1998; 67: 425–479.

    Article  CAS  PubMed  Google Scholar 

  11. Pickart CM, Eddins MJ . Ubiquitin: structures, functions, mechanisms. Biochim Biophys Acta 2004; 1695: 55–72.

    Article  CAS  PubMed  Google Scholar 

  12. Deng S, Zhou H, Xiong R, Lu Y, Yan D, Xing T et al. Over-expression of genes and proteins of ubiquitin specific peptidases (USPs) and proteasome subunits (PSs) in breast cancer tissue observed by the methods of RFDD-PCR and proteomics. Breast Cancer Res Treat 2007; 104: 21–30.

    Article  CAS  PubMed  Google Scholar 

  13. Voorhees PM, Dees EC, O’Neil B, Orlowski RZ . The proteasome as a target for cancer therapy. Clin Cancer Res 2003; 9: 6316–6325.

    CAS  PubMed  Google Scholar 

  14. Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D et al. Clinical factors predictive of outcome with bortezomib in patients with relapsed, refractory multiple myeloma. Blood 2005; 106: 2977–2981.

    Article  CAS  PubMed  Google Scholar 

  15. Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, Facon T et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 2005; 352: 2487–2498.

    Article  CAS  PubMed  Google Scholar 

  16. Dreicer R, Petrylak D, Agus D, Webb I, Roth B . Phase I/II study of bortezomib plus docetaxel in patients with advanced androgen-independent prostate cancer. Clin Cancer Res 2007; 13: 1208–1215.

    Article  CAS  PubMed  Google Scholar 

  17. Kane RC, Dagher R, Farrell A, Ko CW, Sridhara R, Justice R et al. Bortezomib for the treatment of mantle cell lymphoma. Clin Cancer Res 2007; 13 (18 Part 1): 5291–5294.

    Article  CAS  PubMed  Google Scholar 

  18. Su Y, Amiri KI, Horton LW, Yu Y, Ayers GD, Koehler E et al. A phase I trial of bortezomib with temozolomide in patients with advanced melanoma: toxicities, antitumor effects, and modulation of therapeutic targets. Clin Cancer Res 2010; 16: 348–357.

    Article  CAS  PubMed  Google Scholar 

  19. Voortman J, Smit EF, Honeywell R, Kuenen BC, Peters GJ, van de Velde H et al. A parallel dose-escalation study of weekly and twice-weekly bortezomib in combination with gemcitabine and cisplatin in the first-line treatment of patients with advanced solid tumors. Clin Cancer Res 2007; 13: 3642–3651.

    Article  CAS  PubMed  Google Scholar 

  20. Kuratomi G, Komuro A, Goto K, Shinozaki M, Miyazawa K, Miyazono K et al. NEDD4-2 (neural precursor cell expressed, developmentally down-regulated 4–2) negatively regulates TGF-beta (transforming growth factor-beta) signalling by inducing ubiquitin-mediated degradation of Smad2 and TGF-beta type I receptor. Biochem J 2005; 386 (Part 3): 461–470.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Lee C, Sintich SM, Mathews EP, Shah AH, Kundu SD, Perry KT et al. Transforming growth factor-beta in benign and malignant prostate. Prostate 1999; 39: 285–290.

    Article  CAS  PubMed  Google Scholar 

  22. Wikstrom P, Bergh A, Damber JE . Transforming growth factor-beta1 and prostate cancer. Scand J Urol Nephrol 2000; 34: 85–94.

    Article  CAS  PubMed  Google Scholar 

  23. Park JI, Lee MG, Cho K, Park BJ, Chae KS, Byun DS et al. Transforming growth factor-beta1 activates interleukin-6 expression in prostate cancer cells through the synergistic collaboration of the Smad2, p38-NF-kappaB, JNK, and Ras signalling pathways. Oncogene 2003; 22: 4314–4332.

    Article  CAS  PubMed  Google Scholar 

  24. Yang J, Wahdan-Alaswad R, Danielpour D . Critical role of Smad2 in tumor suppression and transforming growth factor-beta-induced apoptosis of prostate epithelial cells. Cancer Res 2009; 69: 2185–2190.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Qi H, Grenier J, Fournier A, Labrie C . Androgens differentially regulate the expression of NEDD4L transcripts in LNCaP human prostate cancer cells. Mol Cell Endocrinol 2003; 210: 51–62.

    Article  CAS  PubMed  Google Scholar 

  26. Hu XY, Xu YM, Fu Q, Yu JJ, Huang J . Nedd4L expression is downregulated in prostate cancer compared to benign prostatic hyperplasia. Eur J Surg Oncol 2009; 35: 527–531.

    Article  CAS  PubMed  Google Scholar 

  27. Nonn L, Ananthanarayanan V, Gann PH . Evidence for field cancerization of the prostate. Prostate 2009; 69: 1470–1479.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Lin X, Liang M, Feng XH . Smurf2 is a ubiquitin E3 ligase mediating proteasome-dependent degradation of Smad2 in transforming growth factor-beta signaling. J Biol Chem 2000; 275: 36818–36822.

    Article  CAS  PubMed  Google Scholar 

  29. Fukuchi M, Fukai Y, Masuda N, Miyazaki T, Nakajima M, Sohda M et al. High-level expression of the Smad ubiquitin ligase Smurf2 correlates with poor prognosis in patients with esophageal squamous cell carcinoma. Cancer Res 2002; 62: 7162–7165.

    CAS  PubMed  Google Scholar 

  30. Chen C, Matesic LE . The Nedd4-like family of E3 ubiquitin ligases and cancer. Cancer Metastasis Rev 2007; 26: 587–604.

    Article  CAS  PubMed  Google Scholar 

  31. Fukunaga E, Inoue Y, Komiya S, Horiguchi K, Goto K, Saitoh M et al. Smurf2 induces ubiquitin-dependent degradation of Smurf1 to prevent migration of breast cancer cells. J Biol Chem 2008; 283: 35660–35667.

    Article  CAS  PubMed  Google Scholar 

  32. Nakano A, Koinuma D, Miyazawa K, Uchida T, Saitoh M, Kawabata M et al. Pin1 down-regulates transforming growth factor-beta (TGF-beta) signaling by inducing degradation of Smad proteins. J Biol Chem 2009; 284: 6109–6115.

    Article  CAS  PubMed  Google Scholar 

  33. Jin C, Yang YA, Anver MR, Morris N, Wang X, Zhang YE . Smad ubiquitination regulatory factor 2 promotes metastasis of breast cancer cells by enhancing migration and invasiveness. Cancer Res 2009; 69: 735–740.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Kaminska B, Wesolowska A, Danilkiewicz M . TGF beta signalling and its role in tumour pathogenesis. Acta Biochim Pol 2005; 52: 329–337.

    CAS  PubMed  Google Scholar 

  35. Perttu MC, Martikainen PM, Huhtala HS, Blauer M, Tammela TL, Tuohimaa PJ et al. Altered levels of Smad2 and Smad4 are associated with human prostate carcinogenesis. Prostate Cancer Prostatic Dis 2006; 9: 185–189.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank the staff of the Laboratory and the Department of Urology of University Hospital Hamburg-Eppendorf, Hamburg, Germany. We express special gratitude to Karin Beutel, Anne Bildhauer, Petra Dase, Hannelore Ellinghausen, Andrea Speckmann and Hannelore Suck for their enthusiasm and excellent technical support. This project was supported by the German Federal Ministry of Education and Science in the framework of the programme for medical genome research (FKZ: 01GS0890 and 01GS08189). We are responsible for the contents of this publication.

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Author notes

  1. O J C Hellwinkel and L E Asong: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Legal Medicine, University Hospital Hamburg-Eppendorf, Hamburg, Germany

    O J C Hellwinkel

  2. Martini-Klinik, Prostate Cancer Center, University Hospital Hamburg-Eppendorf, Hamburg, Germany

    O J C Hellwinkel, C Wagner & T Schlomm

  3. Department of Urology, University Hospital Hamburg-Eppendorf, Hamburg, Germany

    L E Asong, J-P Rogmann & C Eichelberg

  4. Division of Molecular Genetics, Working Group Cancer Genome Research, German Cancer Research Center, Heidelberg, Germany

    H Sültmann

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  1. O J C Hellwinkel
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Correspondence to O J C Hellwinkel.

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Hellwinkel, O., Asong, L., Rogmann, JP. et al. Transcription alterations of members of the ubiquitin–proteasome network in prostate carcinoma. Prostate Cancer Prostatic Dis 14, 38–45 (2011). https://doi.org/10.1038/pcan.2010.48

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