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 14-3-3σ gene was detected in the cell line LNCaP. 14-3-3σ 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 14-3-3σ in all 41 primary PCa samples analysed, which was accompanied by a decrease or loss of 14-3-3σ protein expression. In contrast, normal prostate epithelial and benign prostate hyperplasia cells showed high levels of 14-3-3σ expression. PCa-precursor lesions (prostatic intraepithelial neoplasia) also displayed decreased levels of 14-3-3σ expression in luminal cells, which are known to contain shortened telomeres. RNA interference-mediated inactivation of 14-3-3σ compromised a DNA damage-induced G2/M arrest in the PCa cell line PC3. The generality of CpG methylation and downregulation of 14-3-3σ 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.
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Acknowledgements
We thank Rene Bernards and Reuven Agami for providing the pSUPER constructs, Antje Menssen and Axel Ullrich for cell lines. Work in Heiko Hermeking's lab is supported by the Max-Planck-Society, the Rudolf-Bartling-Stiftung and the Deutsche Krebshilfe/Dr Mildred-Scheel-Stiftung.
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Lodygin, D., Diebold, J. & Hermeking, H. Prostate cancer is characterized by epigenetic silencing of 14-3-3σ expression. Oncogene 23, 9034–9041 (2004). https://doi.org/10.1038/sj.onc.1208004
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DOI: https://doi.org/10.1038/sj.onc.1208004
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