Gene expression and epigenetic discovery screen reveal methylation of SFRP2 in prostate cancer.
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.
Prostate Molecular Oncology, Department of Clinical Medicine, Institute of Molecular Medicine, Trinity College Dublin, Ireland. aperry@tcd.ie
Antoinette S
AS
Perry
Gillian
G
O'Hurley
Omer A
OA
Raheem
Kevin
K
Brennan
Simon
S
Wong
Anthony
A
O'Grady
Anne-Marie
AM
Kennedy
Laure
L
Marignol
Therese M
TM
Murphy
Linda
L
Sullivan
Ciara
C
Barrett
Barbara
B
Loftus
John
J
Thornhill
Stephen M
SM
Hewitt
Mark
M
Lawler
Elaine
E
Kay
Thomas
T
Lynch
Donal
D
Hollywood
D000328:Adult; D000368:Aged; D045744:Cell Line, Tumor; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000094742:Secreted Frizzled-Related Proteins
D008565:Membrane Proteins; C109618:SFRP2 protein, human; D000094742:Secreted Frizzled-Related Proteins