Functional epigenomics identifies genes frequently silenced in prostate cancer

• Published in: Cancer research (Chicago, Ill.) Vol. 65; no. 10; pp. 4218 - 4227
• Main Authors: LODYGIN, Dimitri, EPANCHINTSEV, Alexey, MENSSEN, Antje, DIEBOLD, Joachim, HERMEKING, Heiko
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15-05-2005
• Subjects: Antineoplastic agents; Biological and medical sciences; Cell Line, Tumor; CpG Islands; DNA Methylation; Gene Expression Regulation, Neoplastic; Gene Silencing; Gynecology. Andrology. Obstetrics; Humans; Intercellular Signaling Peptides and Proteins - biosynthesis; Intercellular Signaling Peptides and Proteins - genetics; Male; Male genital diseases; Medical sciences; Membrane Proteins - biosynthesis; Membrane Proteins - genetics; Nephrology. Urinary tract diseases; Oligonucleotide Array Sequence Analysis; Pharmacology. Drug treatments; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Proteins - genetics; Proteins - metabolism; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland; Urinary system disease; Prostate disease; Gene; Genetics; Malignant tumor; Male genital diseases; Prostate cancer
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-04-4407

In many cases, silencing of gene expression by CpG methylation is causally involved in carcinogenesis. Furthermore, cancer-specific CpG methylation may serve as a tumor marker. In order to identify candidate genes for inactivation by CpG methylation in prostate cancer, the prostate cancer cell lines LNCaP, PC3, and Du-145 were treated with 5-aza-2' deoxycytidine and trichostatin A, which leads to reversion of epigenetic silencing. By microarray analysis of 18,400 individual transcripts, several hundred genes were found to be induced when compared with cells treated with trichostatin A. Fifty re-expressed genes were selected for further analysis based on their known function, which implied a possible involvement in tumor suppression. Twelve of these genes showed a significant degree of CpG methylation in their promoters. Six genes were silenced by CpG methylation in the majority of five analyzed prostate cancer cell lines, although they displayed robust mRNA expression in normal prostate epithelial cells obtained from four different donors. In primary prostate cancer samples derived from 41 patients, the frequencies of CpG methylation detected in the promoter regions of these genes were: GPX3, 93%; SFRP1, 83%; COX2, 78%; DKK3, 68%; GSTM1, 58%; and KIP2/p57, 56%. Ectopic expression of SFRP1 or DKK3 resulted in decreased proliferation. The expression of DKK3 was accompanied by attenuation of the mitogen-activated protein kinase pathway. The high frequency of CpG methylation detected in the promoters of the identified genes suggests a potential causal involvement in prostate cancer and may prove useful for diagnostic purposes.