2018 Fiscal Year Final Research Report
Epigenetic regulation of the epithelial integrity by p53
| Project/Area Number |
16K08569
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
General medical chemistry
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| Research Institution | Hokkaido University |
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Principal Investigator |
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Keywords | p53 / 上皮間葉転換 / ヒストン修飾 / EZH2 |
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| Outline of Final Research Achievements |
Analyses of various cancer cells have demonstrated a statistical correlation between TP53 mutations and the infringement of epithelial phenotypes, suggesting that some epithelial cells require TP53 to maintain their integrity. Likewise, the ENCODE project indicates the enrichment of putative p53 binding motifs within the regulatory regions of epithelial genes. However, the roles of p53 in epithelial integrity still largely remain elusive. We showed that epithelial genes may require normal-p53 to encounter EZH2. The loss of normal-p53 induced EZH2-mediated H3K27me3 deposition at histones regulating epithelial genes, such as CDH1. p53 can access this locus in epithelial cells but not in mesenchymal cells. Our results in vitro and from TCGA datasets indicated that H3K27me3 deposition by the loss of p53 is specific to epithelial genes. Our results identified an uncharted function of normal-p53 to protect epithelial genes from EZH2-mediated repression to maintain epithelial integrity.
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| Free Research Field |
細胞生物学
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| Academic Significance and Societal Importance of the Research Achievements |
本研究では、長期培養した幾つかのヒト癌細胞株やヒト正常乳腺上皮細胞を用いた解析から、上皮形質の維持機構に多様性、もしくは、多層性がある可能性を強く示唆した。このような多様性が培養細胞だけでなく正常組織にも存在する普遍的なものであるならば、癌研究だけでなく、iPS技術などを用いる再生医療の安全性にも深く考慮されるべき、未解明の上皮形質維持機構が存在することになる。
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