Abstract
Abstract Cancer is one of the most prevalent age-associated diseases in elderly populations and is largely attributed to accumulation of genetic mutations secondary to the loss of tumor suppressive functions. p53 is a potent tumor suppressor that is implicated in organismal aging in vivo and replicative senescence in vitro; however, its transcriptional regulation during replicative senescence in cells remain unclear. The current study was undertaken to examine the epigenetic regulation of p53 transcription during replicative senescence in normal human keratinocytes. Normal human oral keratinocytes (NHOKs) undergoing senescence upon serial subcultures exhibited a decrease in p53 gene expression. Methylation status of two CpG islands in the p53 promoter was evaluated by treating with 5-aza-CdR, a demethylating agent, and by using bisulfite methylation sequencing analysis. Status of histone modification was evaluated using Chromatin Immunoprecipitation (ChIP) assay with anti-H3K27me3, a repressive mark, and anti-H3Ac, an active mark at the 5 different sites of the p53 promoter regions. In the presence of 5-aza-CdR, there was no increase in p53 expression in senescent NHOK at both mRNA and protein level. Bisulfite-sequencing analysis revealed no methylation changes at the CpG islands in the p53 promoters from young and senescent NHOK. However, during replicative senescence in NHOK, there were notable enrichment of anti-H3K27me3 occupancy and significant decrease in anti-H3Ac occupancy in the p53 promoter regions, indicating that chromatin at the p53 locus undergo compaction during replicative senescence. Our study demonstrates that the diminution of p53 during replicative senescence is epigenetically regulated in human keratinocytes. Citation Format: Reuben H. Kim, Mo K. Kang, Terresa Kim, Paul Yang, Christine Hong, Ki-Hyuk Shin, No-Hee Park. p53 gene expression is epigenetically regulated during replicative senescence in keratinocytes. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2256. doi:10.1158/1538-7445.AM2014-2256
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