Journal of Molecular Medicine

, Volume 84, Issue 11, pp 911–918

Hypermethylation of Cyclin D2 is associated with loss of mRNA expression and tumor development in prostate cancer

  • Rui Henrique
  • Vera Lúcia Costa
  • Nuno Cerveira
  • André Lopes Carvalho
  • Mohammad Obaidul Hoque
  • Franclim Ricardo Ribeiro
  • Jorge Oliveira
  • Manuel Rodrigues Teixeira
  • David Sidransky
  • Carmen Jerónimo
Original Article

Abstract

D-type cyclins play a pivotal role in cell cycle regulation and their abnormal expression was associated with several human malignancies. To assess Cyclin D2 promoter methylation status and expression levels in prostate tissues, quantitative methylation-specific PCR and quantitative reverse transcription PCR assays were performed in a large series of prostate carcinomas, high-grade prostatic intraepithelial neoplasias (HGPIN), benign prostate hyperplasias (BPH), normal prostate tissue (NPT) samples, and prostate cancer (PCa) cell lines (before and after demethylating treatment). Methylation levels were correlated with mRNA expression levels and key clinicopathologic parameters. Cyclin D2 promoter methylation was found in 117/118 PCa, 38/38 HGPIN, 24/30 BPH, 11/11 NPT, and 4/4 cell lines. Methylation levels were significantly higher in PCa compared with HGPIN, NPT, and BPH (P<0.0001), correlating with tumor stage and Gleason score (r=0.29, P=0.0014; and r=0.32, P=0.0005, respectively). Conversely, Cyclin D2 mRNA levels were significantly lower in PCa (P<0.01) and a significant inverse correlation between Cyclin D2 methylation and expression levels was found in prostatic tissues (r=−0.61, P<0.000001). Demethylating treatment induced a substantial increase in Cyclin D2 mRNA in LNCaP cells whereas decreased levels were observed in DU-145 and PC-3 cells. We concluded that Cyclin D2 promoter methylation downregulates gene transcription and occurs with high frequency at low levels in normal, hyperplastic, and preneoplastic prostate tissues. Conversely, high Cyclin D2 methylation levels characterize invasive prostatic carcinoma, correlating with clinicopathologic features of tumor aggressiveness.

Keywords

Cyclin D2 Epigenetics Expression Methylation Prostate cancer Quantitative MSP Quantitative RT-PCR 

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Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Rui Henrique
    • 1
    • 4
  • Vera Lúcia Costa
    • 2
  • Nuno Cerveira
    • 2
  • André Lopes Carvalho
    • 5
  • Mohammad Obaidul Hoque
    • 5
  • Franclim Ricardo Ribeiro
    • 2
  • Jorge Oliveira
    • 3
  • Manuel Rodrigues Teixeira
    • 2
    • 4
  • David Sidransky
    • 5
  • Carmen Jerónimo
    • 2
    • 4
    • 6
  1. 1.Department of PathologyPortuguese Oncology Institute, PortoPortoPortugal
  2. 2.Department of GeneticsPortuguese Oncology Institute, PortoPortoPortugal
  3. 3.Department of UrologyPortuguese Oncology Institute, PortoPortoPortugal
  4. 4.Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel SalazarUniversity of PortoPortoPortugal
  5. 5.Department of Otolaryngology—Head and Neck Surgery, Head and Neck Cancer Research DivisionJohns Hopkins University School of MedicineBaltimoreUSA
  6. 6.Fernando Pessoa University School of Health SciencesPortoPortugal

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