title: Formaldehyde-induced histone H3 phosphorylation via JNK and the expression of proto-oncogenes.
abstract: Formaldehyde (FA) is a very reactive compound that forms DNA adducts and DNA-protein crosslinks, which are known to contribute to FA-induced mutations and carcinogenesis. Post-translational modifications to histones have recently attracted attention due to their link with cancer. In the present study, we examined histone modifications following a treatment with FA. FA significantly phosphorylated histone H3 at serine 10 (H3S10), and at serine 28 (H3S28), the time-course of which was similar to the phosphorylation of H2AX at serine 139 (γ-H2AX), a marker of DNA double strand breaks. The temporal deacetylation of H3 was observed due to the reaction of FA with the lysine residues of histones. The phosphorylation mechanism was then analyzed by focusing on H3S10. The nuclear distribution of the phosphorylation of H3S10 and γ-H2AX did not overlap, and the phosphorylation of H3S10 could not be suppressed with an inhibitor of ATM/ATR, suggesting that the phosphorylation of H3S10 was independent of the DNA damage response. ERK and JNK in the MAPK pathways were phosphorylated by the treatment with FA, in which the JNK pathway was the main target for phosphorylation. The phosphorylation of H3S10 increased at the promoter regions of c-fos and c-jun, indicating a relationship between FA-induced tumor promotion activity and phosphorylation of H3S10. These results suggested that FA both initiates and promotes cancer, as judged by an analysis of histone modifications.
authors.affiliation: Graduate Division of Nutritional and Environmental Sciences, University of Shizuoka, Shizuoka, Japan.
authors.forename: Ikuma
authors.initials: I
authors.lastname: Yoshida
authors.affiliation: Graduate Division of Nutritional and Environmental Sciences, University of Shizuoka, Shizuoka, Japan. Electronic address: ibuki@u-shizuoka-ken.ac.jp.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Ibuki
mesh_terms: D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D004249:DNA Damage / Q000187:drug effects; D005557:Formaldehyde / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D006657:Histones / Q000378:metabolism*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D000090063:Proto-Oncogene Mas; D011519:Proto-Oncogenes / Q000235:genetics*; D017382:Reactive Oxygen Species / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D006657:Histones; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D017382:Reactive Oxygen Species; D005557:Formaldehyde; D048031:JNK Mitogen-Activated Protein Kinases
keywords: Formaldehyde; Histone H3; JNK; Phosphorylation; Proto-oncogene; γ-H2AX