Journal of Molecular Medicine

, Volume 88, Issue 9, pp 953–962

Role of DNA methyltransferase 1 in hormone-resistant prostate cancer

  • Miao-Fen Chen
  • Wen-Cheng Chen
  • Yu-Jia Chang
  • Ching-Fang Wu
  • Chun-Te Wu
Original Article

Abstract

Given the poor outcome of patients with hormone-resistant (HR) prostate cancer, new strategies are needed to improve the current therapeutic regimens and/or develop novel treatments. We therefore aimed to provide a better understanding of the molecular mechanisms involved in the aggressive tumor behavior of HR and develop more rational anti-tumor therapies. Three HR prostate cancer cell lines (androgen receptor (AR)-positive LNCaP-HR and 22RV1-HR and AR-negative PC-3) were used. Changes in tumor behavior, treatment response, and related signaling in HR were investigated in vitro and in vivo. The results revealed that constitutional activation of STAT3 and overexpressions of DNMT1 were important in the transition of HR prostate cancer. Furthermore, DNMT1 expression was required for the maintenance of STAT3 activation. When DNMT1 activity in HR was blocked, aggressive tumor behavior and treatment resistance could be overcome, which was seen in both in vitro and in vivo experiments. The underlying changes associated with inhibited DNMT1 included less epithelial–mesenchymal changes, less invasion ability, slower tumor growth, and impaired DNA repair ability, which are independent of AR and p53 status. In conclusion, altered DNMT1 expression associated with activated STAT3 may be crucial in the transition of HR. Targeting DNMT1 could be a promising strategy for the treatment of HR prostate, as evidenced by inhibited tumor growth and enhanced radiosensitivity. These findings provide evidence for therapeutically targeting DNMT1 in HR prostate cancer.

Keywords

DNMT1 STAT3 Radiation Hormone-resistant prostate cancer 

Supplementary material

109_2010_640_MOESM1_ESM.pdf (834 kb)
ESM 1(PDF 834 kb)

References

  1. 1.
    Craft N, Chhor C, Tran C et al (1999) Evidence for clonal outgrowth of androgen-independent prostate cancer cells from androgen-dependent tumors through a two-step process. Cancer Res 59:5030–5036PubMedGoogle Scholar
  2. 2.
    Tilley WD, Buchanan G, Hickey TE et al (1996) Mutations in the androgen receptor gene are associated with progression of human prostate cancer to androgen independence. Clin Cancer Res 2:277–285PubMedGoogle Scholar
  3. 3.
    Scher HI, Buchanan G, Gerald W et al (2004) Targeting the androgen receptor: improving outcomes for castration-resistant prostate cancer. Endocr Relat Cancer 11:459–476CrossRefPubMedGoogle Scholar
  4. 4.
    Herman JG, Baylin SB (2003) Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med 349:2042–2054CrossRefPubMedGoogle Scholar
  5. 5.
    Robertson KD (2002) DNA methylation and chromatin—unraveling the tangled web. Oncogene 21:5361–5379CrossRefPubMedGoogle Scholar
  6. 6.
    Baylin SB, Herman JG (2000) DNA hypermethylation in tumorigenesis: epigenetics joins genetics. Trends Genet 16:168–174CrossRefPubMedGoogle Scholar
  7. 7.
    Kim WY, Sharpless NE (2006) The regulation of INK4/ARF in cancer and aging. Cell 127:265–275CrossRefPubMedGoogle Scholar
  8. 8.
    Wu CT, Chen WC, Liao SK, Hsu CL, Lee KD, Chen MF (2007) The radiation response of hormone-resistant prostate cancer induced by long-term hormone therapy. Endocr Relat Cancer 14:633–643CrossRefPubMedGoogle Scholar
  9. 9.
    Chen CD, Welsbie DS, Tran C et al (2004) Molecular determinants of resistance to antiandrogen therapy. Nat Med 10:33–39CrossRefPubMedGoogle Scholar
  10. 10.
    Edwards J, Bartlett JM (2005) The androgen receptor and signal-transduction pathways in hormone-refractory prostate cancer. Part 2: androgen-receptor cofactors and bypass pathways. BJU Int 95:1327–1335CrossRefPubMedGoogle Scholar
  11. 11.
    Edwards J, Bartlett JM (2005) The androgen receptor and signal-transduction pathways in hormone-refractory prostate cancer. Part 1: modifications to the androgen receptor. BJU Int 95:1320–1326CrossRefPubMedGoogle Scholar
  12. 12.
    Kinkade CW, Castillo-Martin M, Puzio-Kuter A et al (2008) Targeting AKT/mTOR and ERK MAPK signaling inhibits hormone-refractory prostate cancer in a preclinical mouse model. J Clin Invest 118:3051–3064PubMedGoogle Scholar
  13. 13.
    Culig Z, Steiner H, Bartsch G et al (2005) Mechanisms of endocrine therapy-responsive and -unresponsive prostate tumours. Endocr Relat Cancer 12:229–244CrossRefPubMedGoogle Scholar
  14. 14.
    Wallner L, Dai J, Escara-Wilke J et al (2006) Inhibition of interleukin-6 with CNTO328, an anti-interleukin-6 monoclonal antibody, inhibits conversion of androgen-dependent prostate cancer to an androgen-independent phenotype in orchiectomized mice. Cancer Res 66:3087–3095CrossRefPubMedGoogle Scholar
  15. 15.
    Gravdal K, Halvorsen OJ, Haukaas SA et al (2007) A switch from E-cadherin to N-cadherin expression indicates epithelial to mesenchymal transition and is of strong and independent importance for the progress of prostate cancer. Clin Cancer Res 13:7003–7011CrossRefPubMedGoogle Scholar
  16. 16.
    Thiery JP (2002) Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer 2:442–454CrossRefPubMedGoogle Scholar
  17. 17.
    Zhang Q, Wang HY, Woetmann A, Raghunath PN, Odum N, Wasik MA (2006) STAT3 induces transcription of the DNA methyltransferase 1 gene (DNMT1) in malignant T lymphocytes. Blood 108:1058–1064CrossRefPubMedGoogle Scholar
  18. 18.
    Zhang Q, Wang HY, Marzec M, Raghunath PN, Nagasawa T, Wasik MA (2005) STAT3- and DNA methyltransferase 1-mediated epigenetic silencing of SHP-1 tyrosine phosphatase tumor suppressor gene in malignant T lymphocytes. Proc Natl Acad Sci USA 102:6948–6953CrossRefPubMedGoogle Scholar
  19. 19.
    Hodge DR, Cho E, Copeland TD, Guszczynski T, Yang E, Seth AK, Farrar WL (2007) IL-6 enhances the nuclear translocation of DNA cytosine-5-methyltransferase 1 (DNMT1) via phosphorylation of the nuclear localization sequence by the AKT kinase. Cancer Genomics Proteomics 4:387–398PubMedGoogle Scholar
  20. 20.
    Niu Y, Altuwaijri S, Lai KP, Wu CT, Ricke WA, Messing EM, Yao J, Yeh S, Chang C (2008) Androgen receptor is a tumor suppressor and proliferator in prostate cancer. Proc Natl Acad Sci USA 105:12182–12187CrossRefPubMedGoogle Scholar
  21. 21.
    Lee JM, Dedhar S, Kalluri R, Thompson EW (2006) The epithelial-mesenchymal transition: new insights in signaling, development, and disease. J Cell Biol 172:973–981CrossRefPubMedGoogle Scholar
  22. 22.
    Chu JH, Yu S, Hayward SW, Chan FL (2009) Development of a three-dimensional culture model of prostatic epithelial cells and its use for the study of epithelial–mesenchymal transition and inhibition of PI3K pathway in prostate cancer. Prostate 69:428–442CrossRefPubMedGoogle Scholar
  23. 23.
    Scher HI, Sawyers CL (2005) Biology of progressive, castration-resistant prostate cancer: directed therapies targeting the androgen-receptor signaling axis. J Clin Oncol 23:8253–8261CrossRefPubMedGoogle Scholar
  24. 24.
    Levy DE, Darnell JE Jr (2002) Stats: transcriptional control and biological impact. Nat Rev Mol Cell Biol 3:651–662CrossRefPubMedGoogle Scholar
  25. 25.
    Culig Z, Steiner H, Bartsch G, Hobisch A (2005) Interleukin-6 regulation of prostate cancer cell growth. J Cell Biochem 95:497–505CrossRefPubMedGoogle Scholar
  26. 26.
    Jones PA, Baylin SB (2002) The fundamental role of epigenetic events in cancer. Nat Rev Genet 3:415–428CrossRefPubMedGoogle Scholar
  27. 27.
    Morey SR, Smiraglia DJ, James SR, Yu J, Moser MT, Foster BA, Karpf AR (2006) DNA methylation pathway alterations in an autochthonous murine model of prostate cancer. Cancer Res 66:11659–11667CrossRefPubMedGoogle Scholar
  28. 28.
    Morey Kinney SR, Smiraglia DJ, James SR, Moser MT, Foster BA, Karpf AR (2008) Stage-specific alterations of DNA methyltransferase expression, DNA hypermethylation, and DNA hypomethylation during prostate cancer progression in the transgenic adenocarcinoma of mouse prostate model. Mol Cancer Res 6:1365–1374CrossRefPubMedGoogle Scholar
  29. 29.
    Lin J, Tang H, Jin X, Jia G, Hsieh JT (2002) p53 regulates Stat3 phosphorylation abd DNA binding activity in human prostate cancer cells expressing constitutively active Stat3. Oncogene 21:3082–3088CrossRefPubMedGoogle Scholar
  30. 30.
    Hu H, Lee HJ, Jiang C, Zhang J, Wang L, Zhao Y, Xiang Q, Lee EO, Kim SH, Lu J (2008) Penta-1, 2, 3, 4, 6-O-galloyl-beta-d-glucose induces p53 and inhibits STAT3 in prostate cancer cells in vitro and suppresses prostate xenograft tumor growth in vivo. Mol Cancer Ther 7:2681–2691, prostate cancer. Cancer 112:1660–1671CrossRefPubMedGoogle Scholar
  31. 31.
    Sonpavde G, Hutson TE, Berry WR (2006) Hormone refractory prostate cancer: management and advances. Cancer Treat Rev 32:90–100CrossRefPubMedGoogle Scholar
  32. 32.
    Uzzo RG, Haas NB, Crispen PL, Kolenko VM (2008) Mechanisms of apoptosis resistance and treatment strategies to overcome them in hormone-refractory prostate cancer. Cancer 112:1660–1671CrossRefPubMedGoogle Scholar
  33. 33.
    Garner E, Raj K (2008) Protective mechanisms of p53-p21-pRb proteins against DNA damage-induced cell death. Cell Cycle 7:277–282PubMedGoogle Scholar
  34. 34.
    Brown JM, Attardi LD (2005) The role of apoptosis in cancer development and treatment response. Nat Rev Cancer 5:231–237CrossRefPubMedGoogle Scholar
  35. 35.
    Olive PL, Banath JP (2004) Phosphorylation of histone H2AX as a measure of radiosensitivity. Int J Radiat Oncol Biol Phys 58:331–335PubMedGoogle Scholar
  36. 36.
    Mortusewicz O, Schermelleh L, Walter J, Cardoso MC, Leonhardt H (2005) Recruitment of DNA methyltransferase I to DNA repair sites. Proc Natl Acad Sci USA 102:8905–8909CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Miao-Fen Chen
    • 1
    • 3
  • Wen-Cheng Chen
    • 1
    • 3
  • Yu-Jia Chang
    • 4
  • Ching-Fang Wu
    • 2
    • 3
  • Chun-Te Wu
    • 2
    • 3
  1. 1.Department of Radiation OncologyChang Gung Memorial HospitalTaipeiTaiwan
  2. 2.Department of UrologyChang Gung Memorial HospitalTaipeiTaiwan
  3. 3.Chang Gung University College of Medicine and Chang Gung Institute of TechnologyTaipeiTaiwan
  4. 4.Department of SurgeryTaipei Medical University and HospitalTaipeiTaiwan

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