Prostate cancer is characterized by epigenetic silencing of 14-3-3σ expression

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Abstract
In order to identify tumor suppressive genes silenced by CpG methylation in prostate carcinoma (PCa), we determined genome-wide expression changes after pharmacological reversal of CpG methylation-mediated transcriptional repression in three PCa cell lines using microarray analysis. Thereby, epigenetic silencing of the 14-3-3 gene was detected in the cell line LNCaP. 14-3-3 encodes a p53-regulated inhibitor of cell cycle progression. Laser microdissection was used to isolate different cell types present in diseased prostatic tissue. Subsequent methylation-specific PCR analysis showed CpG methylation of 14-3-3 in all 41 primary PCa samples analysed, which was accompanied by a decrease or loss of 14-3-3 protein expression. In contrast, normal prostate epithelial and benign prostate hyperplasia cells showed high levels of 14-3-3 expression. PCa-precursor lesions (prostatic intraepithelial neoplasia) also displayed decreased levels of 14-3-3 expression in luminal cells, which are known to contain shortened telomeres. RNA interference-mediated inactivation of 14-3-3 compromised a DNA damage-induced G2/M arrest in the PCa cell line PC3. The generality of CpG methylation and downregulation of 14-3-3 expression in PCa suggests that it significantly contributes to the formation of PCa, potentially by allowing the escape from a DNA damage-induced arrest elicited by telomere shortening.