Epigenetic suppression of the anti-aging gene KLOTHO in human prostate cancer cell lines |
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Authors: | Minkyu Seo Min Su Kim Ara Jang Hyun Joo Chung Yoohun Noh Do-Hee Kim |
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Institution: | 1. Department of Urology, Chung-Ang University College of Medicine, Seoul, Republic of Korea;2. Department of Urology, Seoul Medical Center, Seoul, Republic of Korea;3. Advanced Urogenital Diseases Research Center, Chung-Ang University College of Medicine, Seoul, Republic of Korea;4. Bio-Integration Research Center for Nutra-Pharmaceutical Epigenetics, Chung-Ang University, Seoul, Republic of Korea;5. Department of Anatomy and Cell Biology and Neurology, College of Medicine, Chung-Ang University, Seoul, Korea;6. Famenity Biomedical Research Center, Famenity, Inc., Gyeonggi, Korea;7. Natural Pharmaceutical R&8. D Center, Naturesense, Inc., Gyeonggi, Korea |
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Abstract: | KLOTHO was originally identified as an aging-suppressor gene that causes a human aging-like phenotype when tested in KLOTHO-deficient-mice. Recent evidence suggests that KLOTHO functions as a tumor suppressor by inhibiting Wnt signaling. KLOTHO gene silencing, including DNA methylation, has been observed in some human cancers. Aberrant activation of Wnt signaling plays a significant role in aging, and its silencing may be related to prostate cancer and other types of cancers. Thus, we investigated whether the expression of the anti-aging gene KLOTHO was associated with epigenetic changes in prostate cancer cell lines. KLOTHO mRNA was detected in the 22Rv1 cell line while it was not detected in DU145 and PC-3 cell lines. The restoration of KLOTHO mRNA in the DU145 and PC-3 cell lines was induced with a DNA methyltransferase inhibitor. Methylation-specific PCR was performed to determine the specific CpG sites in the KLOTHO promoter responsible for expression. In addition, the level of methylation was assessed in each CpG by performing bisulfite sequencing and quantitative pyrosequencing analysis. The results suggested a remarkable inverse relationship between KLOTHO expression and promoter methylation in prostate cancer cell lines. |
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Keywords: | Prostate cancer aging KLOTHO epigenetic inactivation DNA methylation |
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