Gene expression and epigenetic discovery screen reveal methylation of SFRP2 in prostate cancer

Antoinette S Perry, Gillian O'Hurley, Omer A Raheem, Kevin Brennan, Simon Wong, Anthony O'Grady, Anne-Marie Kennedy, Laure Marignol, Therese Murphy, Linda Sullivan, Ciara Barrett, Barbara Loftus, John Thornhill, Stephen M Hewitt, Mark Lawler, Elaine Kay, Thomas Lynch, Donal Hollywood, Mark Lawler

Research output: Contribution to journalArticlepeer-review

34 Citations (Scopus)

Abstract

Aberrant activation of Wnts is common in human cancers, including prostate. Hypermethylation associated transcriptional silencing of Wnt antagonist genes SFRPs (Secreted Frizzled-Related Proteins) is a frequent oncogenic event. The significance of this is not known in prostate cancer. The objectives of our study were to (i) profile Wnt signaling related gene expression and (ii) investigate methylation of Wnt antagonist genes in prostate cancer. Using TaqMan Low Density Arrays, we identified 15 Wnt signaling related genes with significantly altered expression in prostate cancer; the majority of which were upregulated in tumors. Notably, histologically benign tissue from men with prostate cancer appeared more similar to tumor (r = 0.76) than to benign prostatic hyperplasia (BPH; r = 0.57, p < 0.001). Overall, the expression profile was highly similar between tumors of high (≥ 7) and low (≤ 6) Gleason scores. Pharmacological demethylation of PC-3 cells with 5-Aza-CdR reactivated 39 genes (≥ 2-fold); 40% of which inhibit Wnt signaling. Methylation frequencies in prostate cancer were 10% (2/20) (SFRP1), 64.86% (48/74) (SFRP2), 0% (0/20) (SFRP4) and 60% (12/20) (SFRP5). SFRP2 methylation was detected at significantly lower frequencies in high-grade prostatic intraepithelial neoplasia (HGPIN; 30%, (6/20), p = 0.0096), tumor adjacent benign areas (8.82%, (7/69), p < 0.0001) and BPH (11.43% (4/35), p < 0.0001). The quantitative level of SFRP2 methylation (normalized index of methylation) was also significantly higher in tumors (116) than in the other samples (HGPIN = 7.45, HB = 0.47, and BPH = 0.12). We show that SFRP2 hypermethylation is a common event in prostate cancer. SFRP2 methylation in combination with other epigenetic markers may be a useful biomarker of prostate cancer.

Original languageEnglish
Pages (from-to)1771-80
Number of pages10
JournalInternational journal of cancer. Journal international du cancer
Volume132
Issue number8
DOIs
Publication statusPublished - 15 Apr 2013

Bibliographical note

Copyright © 2012 UICC.

Keywords

  • Adult
  • Aged
  • Cell Line, Tumor
  • DNA Methylation
  • Epigenesis, Genetic
  • Gene Expression Profiling
  • Humans
  • Male
  • Membrane Proteins
  • Middle Aged
  • Promoter Regions, Genetic
  • Prostatic Neoplasms
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction

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