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

      Perry, Antoinette S; O'Hurley, Gillian; Raheem, Omer A; Brennan, Kevin; Wong, Simon; O'Grady, Anthony; Kennedy, Anne-Marie; Marignol, Laure; Murphy, Therese M; Sullivan, Linda; et al. (2013-04-15)
      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.
    • In silico analysis and DHPLC screening strategy identifies novel apoptotic gene targets of aberrant promoter hypermethylation in prostate cancer.

      Murphy, Therese M; Sullivan, Linda; Lane, Caroline; O'Connor, Lisa; Barrett, Ciara; Hollywood, Donal; Lynch, Thomas; Lawler, Mark; Perry, Antoinette S; Prostate Molecular Oncology, Institute of Molecular Medicine, Trinity College, Dublin, Ireland. murphyth@tcd.ie (Wiley, 2011-01-01)
      Aberrant DNA methylation has been implicated as a key survival mechanism in cancer, whereby promoter hypermethylation silences genes essential for many cellular processes including apoptosis. Limited data is available on the methylation profile of apoptotic genes in prostate cancer (CaP). The aim of this study was to profile methylation of apoptotic-related genes in CaP using denaturing high performance liquid chromatography (DHPLC).
    • Manipulating the epigenome for the treatment of urological malignancies.

      O'Rourke, Colm J; Knabben, Vinicius; Bolton, Eva; Moran, Diarmaid; Lynch, Thomas; Hollywood, Donal; Perry, Antoinette S; Prostate Molecular Oncology, Institute of Molecular Medicine, Trinity College, Dublin, Ireland. (2013-05)
      Urological malignancies (cancers of the prostate, bladder, kidney and testes) account for 15% of all human cancers and more than 500,000 deaths worldwide each year. This group of malignancies is spread across multiple generations, affecting the young (testicular) through middle and old-age (kidney, prostate and bladder). Like most human cancers, urological cancers are characterized by widespread epigenetic insult, causing changes in DNA hypermethylation and histone modifications leading to silencing of tumor suppressor genes and genomic instability. The inherent stability yet dynamic plasticity of the epigenome lends itself well to therapeutic manipulation. Epigenetic changes are amongst the earliest lesions to occur during carcinogenesis and are essentially reversible (unlike mutations). For this reason, much attention has been placed over the past two decades on deriving pharmacological compounds that can specifically target and reverse such epi-mutations, either halting cancer on its developmental trajectory or reverting fully formed cancers to a more clinically manageable state. This review discusses DNA methyltransferase and histone deacetylase inhibitors that have been extensively studied in preclinical models and clinical trials for advanced and metastatic urological cancers.