期刊
JOURNAL OF APPLIED TOXICOLOGY
卷 33, 期 9, 页码 951-958出版社
WILEY
DOI: 10.1002/jat.2765
关键词
arsenic; p16(INK4a); histone H3K9 dimethylation; G9a; liver
类别
资金
- National Institute for Environmental Studies [0710AG333]
- Environment Technology Development Fund by the Ministry of the Environment Japan [KS-01]
- Ministry of Education, Culture, Sports, Science and Technology of Japan [23790680, 23390166]
- Banyu Foundation
- Grants-in-Aid for Scientific Research [23390166, 23790680] Funding Source: KAKEN
Long-term exposure of humans to high concentrations of arsenic is associated with an increased risk of cancer. Previous studies have suggested that arsenic exposure promotes tumorigenesis by inducing changes in the expression of tumor-related genes by dysregulating DNA methylation at tumor-related gene loci. However, the causal relationships between epigenetic changes and both arsenic exposure and tumorigenesis are still unclear. In the present study, we investigated whether arsenic can change the expression of tumor-related genes by inducing epigenetic modifications before tumorigenesis. We did so by investigating the effects of long-term arsenic exposure on representative epigenetic modifications, DNA methylation and histone modifications, in the tumor-free normal liver of C57Bl/6 mice. We focused on the tumor-related genes, p16INK4a, RASSF1A, Ha-ras and ER- as target genes, because their expression and promoter methylation status in mice have been reported to be affected by long-term arsenic exposure. The results showed that long-term arsenic exposure induced a significant decrease in expression of p16INK4a associated with an increase in level of dimethylated histone H3 lysine 9 (H3K9), a transcription-suppressive histone modification, in the promoter region, but that DNA methylation of the promoter region was unaffected. The results also showed a significant increase in recruitment of H3K9 histone methyltransferase G9a to the promoter after arsenic exposure. These findings suggest that long-term arsenic exposure may induce down-regulation of p16INK4a by targeting recruitment of G9a and H3K9 dimethylation without altering DNA methylation before tumorigenesis in the liver. Copyright (c) 2012 John Wiley & Sons, Ltd.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据