Nutlin-3-induced redistribution of chromatin-bound IFI16 in human hepatocellular carcinoma cells in vitro is associated with p53 activation

Aim： Interferon-y inducible protein 16 （IFI16）, a DNA sensor for DNA double-strand break （DSB）, is expressed in most human hepatocellular carcinoma cell （HCC） lines. In this study we investigated the re-localization of chromatin-bound IFI16 by Nutlin-3, a DNA damage agent, in HCC cells in vitro, and...

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Published in:Acta pharmacologica Sinica 2015-02, Vol.36 (2), p.252-258
Main Authors: Shi, Xin-li, Yang, Jing, Mao, Nan, Wu, Jing-hua, Ren, Lai-feng, Yang, Yuan, Yin, Xiao-lin, Wei, Lin, Li, Ming-yuan, Wang, Bao-ning
Format: Article
Language:English
Subjects:
Carcinoma, Hepatocellular - metabolism
Cell Line
Cell Line, Tumor
Chromatin - metabolism
Humans
Imidazoles - pharmacology
Liver Neoplasms - metabolism
Nuclear Proteins - metabolism
Original
p53
Phosphoproteins - metabolism
Piperazines - pharmacology
SMMC-7721细胞
Tumor Suppressor Protein p53 - metabolism
亚细胞定位
人肝癌细胞
体外
再分配
染色质
诱导蛋白
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Summary:Aim： Interferon-y inducible protein 16 （IFI16）, a DNA sensor for DNA double-strand break （DSB）, is expressed in most human hepatocellular carcinoma cell （HCC） lines. In this study we investigated the re-localization of chromatin-bound IFI16 by Nutlin-3, a DNA damage agent, in HCC cells in vitro, and the potential mechanisms. Methods： Human HCC SMMC-7721 （wild-type TP53）, Huh-7 （mutant TP53）, Hep3B （null TP53） and normal fetal liver L02 cell lines were examined. DSB damage in HCC cells was detected via yH2AX expression and foci formation assay. The expression of IFI16 and IFNB mRNA was measured using RT-PCR, and subcellular localization and expression of the IFI16 protein were detected using chromatin fractionation, Western blot analysis, and fluorescence microscopy. Results： Treatment of SMMC-7721 cells with Nutlin-3 （10 pmol/L） or etoposide （40 pmol/L） induced significant DSB damage. In SMMC-7721 cells, Nutlin-3 significantly increased the expression levels of IFI16 and IFNB mRNA, and partially redistributed chromatin- bound IFI16 protein to the cytoplasm. These effects were blocked by pretreatment with pifithrin-a, a p53 inhibitor. Furthermore, Nutlin-3 did not induce ectopic expression of IFI16 protein in Huh-7 and Hep3B cells. Moreover, the association of IFI16 with chromatin and Nutlin-3-induced changes in localization were not detected in L02 cells. Conclusion： Nutlin-3 regulates the subcellular localization of IFI16 in HCC cells in vitro in a p53-dependent manner.
ISSN:1671-4083
1745-7254
DOI:10.1038/aps.2014.106