title: Cadmium induces histone H3 lysine methylation by inhibiting histone demethylase activity.
abstract: Cadmium is an established human lung carcinogen with weak mutagenicity. However, the mechanisms underlying cadmium-induced carcinogenesis remain obscure. It has been suggested that epigenetic mechanisms may play a role in cadmium-induced carcinogenesis. In this study, we investigated the effects of cadmium on histone methylation and histone demethylases, and the role of histone methylation in transformation of immortalized normal human bronchial epithelial (BEAS-2B) cells. Exposure to 0.625, 1.25, 2.5, and 5.0 μM of cadmium for 6, 24, and 48 h increased global trimethylated histone H3 on lysine 4 (H3K4me3) and dimethylated histone H3 on lysine 9 (H3K9me2) in BEAS-2B cells compared with untreated cells, and most of these changes remained after the removal of cadmium (P < .05 or P < .01 for most modifications). Meanwhile, cadmium inhibited the activities of histone H3 on lysine 4 (H3K4) and histone H3 on lysine 9 (H3K9) demethylases which were detected by histone demethylation assay. However, there was no significant change in the protein levels of the H3K4 demethylase lysine-specific demethylase 5A (KDM5A) and the H3K9 demethylase lysine-specific demethylase 3A (KDM3A). Interestingly, during transformation of BEAS-2B cells by 20 weeks of exposure to 2.0 μM cadmium as assessed by anchorage-independent growth in soft agar, global H3K4me3, and H3K9me2 were significantly increased at 4 weeks (P < .05 or P < .01), whereas no significant change was observed at 8, 12, 16, and 20 weeks compared with control. Our study suggests that cadmium increases global H3K4me3 and H3K9me2 by inhibiting the activities of histone demethylases, and aberrant histone methylation that occurs early (48 h) and at 4 weeks is associated with cadmium-induced transformation of BEAS-2B cells at the early stage.
authors: *Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China and Department of Environmental Medicine, New York University School of Medicine, Tuxedo, New York and Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York.
authors: Chunlian
authors: C
authors: Xiao
authors: *Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China and Department of Environmental Medicine, New York University School of Medicine, Tuxedo, New York and Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York.
authors: Yin
authors: Y
authors: Liu
authors: *Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China and Department of Environmental Medicine, New York University School of Medicine, Tuxedo, New York and Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York.
authors: Chengfeng
authors: C
authors: Xie
authors: *Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China and Department of Environmental Medicine, New York University School of Medicine, Tuxedo, New York and Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York.
authors: Wei
authors: W
authors: Tu
authors: *Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China and Department of Environmental Medicine, New York University School of Medicine, Tuxedo, New York and Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York.
authors: Yujie
authors: Y
authors: Xia
authors: *Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China and Department of Environmental Medicine, New York University School of Medicine, Tuxedo, New York and Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York.
authors: Max
authors: M
authors: Costa
authors: *Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China and Department of Environmental Medicine, New York University School of Medicine, Tuxedo, New York and Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York xue.zhou@hust.edu.cn.
authors: Xue
authors: X
authors: Zhou
mesh_terms: D000818:Animals; D002104:Cadmium / Q000633:toxicity*; D002417:Cattle; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000633:toxicity*; D056466:Histone Demethylases / Q000037:antagonists & inhibitors*; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D008239:Lysine / Q000737:chemistry / Q000378:metabolism*; D008745:Methylation
chemical_list: D004791:Enzyme Inhibitors; D006657:Histones; D002104:Cadmium; D056466:Histone Demethylases; D008239:Lysine
keywords: cadmium; carcinogenesis; epigenetics; histone demethylase; histone methylation