Department of Occupational and Environmental Health, Key Laboratory of Environment and Health, Ministry of Education, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, People's Republic of China.
J Appl Toxicol. 2018 Apr;38(4):480-488. doi: 10.1002/jat.3555. Epub 2017 Nov 17.
Arsenic is an established human carcinogen but with weak mutagenic activity. The mechanisms of arsenic-induced carcinogenesis are not well understood. In the present study, we investigated the role of histone methylation in transformation of human bronchial epithelial (BEAS-2B) cells. After 16 weeks' exposure, cells were transformed by 0.1, 0.5 and 1 μm arsenite. Global trimethylated H3K4 (H3K4me3) was decreased by 0.1 μm arsenite at 12 weeks, and 0.5 and 1 μm arsenite at 8, 12 and 16 weeks, which could be attributed to reduced histone methyltransferase activities, increased histone demethylase (HDM) activities as well as increased protein levels of H3K4 demethylase KDM5A. Global dimethylated H3K9 (H3K9me2) was also decreased after exposure to 0.5 μm arsenite for 4, 8, 12 and 16 weeks and 1.0 μm arsenite for 8 and 12 weeks, which was associated with an increase of HDM activities. Our findings indicated that arsenite decreased global H3K4me3 and H3K9me2 levels during cell transformation by modulating the enzymatic activities of histone methyltransferases and/or HDMs, and by upregulation of KDM5A protein levels for H3K4me3.
砷是一种已确定的人类致癌物，但具有较弱的致突变活性。砷诱导致癌的机制尚不清楚。在本研究中，我们研究了组蛋白甲基化在人支气管上皮（BEAS-2B）细胞转化中的作用。暴露 16 周后，用 0.1、0.5 和 1 μm 亚砷酸盐使细胞转化。0.1 μm 亚砷酸盐在 12 周时使全局三甲基化 H3K4（H3K4me3）减少，而 0.5 和 1 μm 亚砷酸盐在 8、12 和 16 周时减少，这可能归因于组蛋白甲基转移酶活性降低、组蛋白去甲基化酶（HDM）活性增加以及 H3K4 去甲基酶 KDM5A 的蛋白水平增加。暴露于 0.5 μm 亚砷酸盐 4、8、12 和 16 周以及 1.0 μm 亚砷酸盐 8 和 12 周后，全局二甲基化 H3K9（H3K9me2）也减少，这与 HDM 活性增加有关。我们的发现表明，亚砷酸盐通过调节组蛋白甲基转移酶和/或 HDM 的酶活性，以及上调 H3K4me3 的 KDM5A 蛋白水平，在细胞转化过程中降低了全局 H3K4me3 和 H3K9me2 水平。
