title: Arsenic Trioxide Reduces Global Histone H4 Acetylation at Lysine 16 through Direct Binding to Histone Acetyltransferase hMOF in Human Cells.
abstract: Histone post-translational modification heritably regulates gene expression involved in most cellular biological processes. Experimental studies suggest that alteration of histone modifications affects gene expression by changing chromatin structure, causing various cellular responses to environmental influences. Arsenic (As), a naturally occurring element and environmental pollutant, is an established human carcinogen. Recently, increasing evidence suggests that As-mediated epigenetic mechanisms may be involved in its toxicity and carcinogenicity, but how this occurs is still unclear. Here we present evidence that suggests As-induced global histone H4K16 acetylation (H4K16ac) partly due to the direct physical interaction between As and histone acetyltransferase (HAT) hMOF (human male absent on first) protein, leading to the loss of hMOF HAT activity. Our data show that decreased global H4K16ac and increased deacetyltransferase HDAC4 expression occurred in arsenic trioxide (As2O3)-exposed HeLa or HEK293T cells. However, depletion of HDAC4 did not affect global H4K16ac, and it could not raise H4K16ac in cells exposed to As2O3, suggesting that HDAC4 might not directly be involved in histone H4K16 de-acetylation. Using As-immobilized agarose, we confirmed that As binds directly to hMOF, and that this interaction was competitively inhibited by free As2O3. Also, the direct interaction of As and C2CH zinc finger peptide was verified by MAIDI-TOF mass and UV absorption. In an in vitro HAT assay, As2O3 directly inhibited hMOF activity. hMOF over-expression not only increased resistance to As and caused less toxicity, but also effectively reversed reduced H4K16ac caused by As exposure. These data suggest a theoretical basis for elucidating the mechanism of As toxicity.
authors.affiliation: School of Life Sciences, Jilin University, Changchun, Jilin 130012, China; School of Pharmacy, Changchun University of Traditional Chinese Medicine, Changchun 130117, China.
authors.forename: Da
authors.initials: D
authors.lastname: Liu
authors.affiliation: School of Life Sciences, Jilin University, Changchun, Jilin 130012, China.
authors.forename: Donglu
authors.initials: D
authors.lastname: Wu
authors.affiliation: School of Life Sciences, Jilin University, Changchun, Jilin 130012, China.
authors.forename: Linhong
authors.initials: L
authors.lastname: Zhao
authors.affiliation: School of Life Sciences, Jilin University, Changchun, Jilin 130012, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: School of Life Sciences, Jilin University, Changchun, Jilin 130012, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Ding
authors.affiliation: School of Life Sciences, Jilin University, Changchun, Jilin 130012, China.
authors.forename: Liguo
authors.initials: L
authors.lastname: Dong
authors.affiliation: School of Life Sciences, Jilin University, Changchun, Jilin 130012, China; Research Center for Drug Metabolism, School of Life Sciences, Jilin University, Changchun 130012, China.
authors.forename: Lianghai
authors.initials: L
authors.lastname: Hu
authors.affiliation: School of Life Sciences, Jilin University, Changchun, Jilin 130012, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Wang
authors.affiliation: School of Life Sciences, Jilin University, Changchun, Jilin 130012, China.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Zhao
authors.affiliation: School of Life Sciences, Jilin University, Changchun, Jilin 130012, China; National Engineering Laboratory for AIDS Vaccine, Jilin University, Changchun City, Jilin 130012, China; Key Laboratory for Molecular Enzymology and Engineering, the Ministry of Education, Jilin University, Changchun City, Jilin 130012, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Cai
authors.affiliation: School of Life Sciences, Jilin University, Changchun, Jilin 130012, China; National Engineering Laboratory for AIDS Vaccine, Jilin University, Changchun City, Jilin 130012, China; Key Laboratory for Molecular Enzymology and Engineering, the Ministry of Education, Jilin University, Changchun City, Jilin 130012, China.
authors.forename: Jingji
authors.initials: J
authors.lastname: Jin
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D004785:Environmental Pollutants / Q000378:metabolism / Q000633:toxicity; D057809:HEK293 Cells; D006367:HeLa Cells; D051548:Histone Acetyltransferases / Q000737:chemistry / Q000378:metabolism*; D006657:Histones / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000378:metabolism*; D010087:Oxides / Q000378:metabolism* / Q000633:toxicity*; D011485:Protein Binding; D016335:Zinc Fingers
chemical_list: D001152:Arsenicals; D004785:Environmental Pollutants; D006657:Histones; D010087:Oxides; D051548:Histone Acetyltransferases; C496552:KAT8 protein, human; D008239:Lysine; D000077237:Arsenic Trioxide