Post-translational modifications in
histones have been associated with
cancer. Although cigarette sidestream
smoke (CSS) as well as mainstream
smoke are
carcinogens, the relationship between carcinogenicity and histone modifications has not yet been clarified. Here, we demonstrated that CSS induced phosphorylation of
histones, involving a carcinogenic process. Treatment with CSS markedly induced the phosphorylation of
histone H3 at
serine 10 and 28 residues (H3S10 and H3S28), which was independent from the cell cycle, in the human pulmonary epithelial cell model, A549 and normal human lung fibroblasts, MRC-5 and WI-38. Using specific inhibitors and
small interfering RNA, the phosphorylation of H3S10 was found to be mediated by
c-jun N-terminal kinase (JNK) and
phosphoinositide 3-kinase (PI3K)/Akt pathways. These pathways were different from that of the CSS-induced phosphorylation of
histone H2AX (γ-H2AX) mediated by
Ataxia telangiectasia-mutated (ATM) and ATM-Rad3-related (ATR)
protein kinases. A
chromatin immunoprecipitation assay revealed that the phosphorylation of H3S10 was increased in the promoter sites of the proto-oncogenes, c-fos and c-jun, which indicated that CSS plays a role in
tumor promotion. Because the phosphorylation of H3S10 was decreased in the
aldehyde-removed CSS and was significantly induced by treatment with
formaldehyde,
aldehydes are suspected to partially contribute to this phosphorylation. These findings suggested that any chemicals in CSS, including
aldehydes, phosphorylate H3S10 via JNK and PI3K/Akt pathways, which is different from the DNA damage response, resulting in
tumor promotion.