title: Persistent phosphorylation at specific H3 serine residues involved in chemical carcinogen-induced cell transformation.
abstract: Identification of aberrant histone H3 phosphorylation during chemical carcinogenesis will lead to a better understanding of the substantial roles of histone modifications in cancer development. To explore whether aberrant H3 phosphorylation contributes to chemical carcinogenesis, we examined the dynamic changes of H3 phosphorylation at various residues in chemical carcinogen-induced transformed human cells and human cancers. We found that histone H3 phosphorylation at Ser10 (p-H3S10) and Ser28 (p-H3S28) was upregulated by 1.5-4.8 folds and 2.1-4.3 folds, respectively in aflatoxin B1-transformed hepatocytes L02 cells (L02RT-AFB1), benzo(a)pyrene-transformed HBE cells (HBERT-BaP), and coke oven emissions-transformed HBE cells (HBERT-COE). The ectopic expression of histone H3 mutant (H3S10A or H3S28A) in L02 cells led to the suppression of an anchorage-independent cell growth as well as tumor formation in immunodeficient mice. In addition, an enhanced p-H3S10 was found in 70.6% (24/34) of hepatocellular carcinoma (HCC), and 70.0% (21/30) of primary lung cancer, respectively. Notably, we found that expression of H3 carrying a mutant H3S10A or H3S28A conferred to cells the ability to maintain a denser chromatin and resistance to induction of DNA damage and carcinogen-induced cell transformation. Particularly, we showed that introduction of a mutant H3S10A abolished the bindings of p-H3S10 to the promoter of DNA repair genes, PARP1 and MLH1 upon AFB1treatment. Furthermore, we revealed that PP2A was responsible for dephosphorylation of p-H3S10. Taken together, these results reveal a key role of persistent H3S10 or H3S28 phosphorylation in chemical carcinogenesis through regulating gene transcription of DNA damage response (DDR) genes.
authors.affiliation: Guangzhou Key Laboratory of Environmental Health and Risk Assessment, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou, China.|Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.|Department of Toxicology, School of Public Health, Guilin Medical University, Guilin, China.
authors.forename: Xiaonian
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Guangzhou Key Laboratory of Environmental Health and Risk Assessment, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou, China.|Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
authors.forename: Daochuan
authors.initials: D
authors.lastname: Li
authors.affiliation: Guangzhou Key Laboratory of Environmental Health and Risk Assessment, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou, China.|Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
authors.forename: Zhengbao
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Toxicology, Guangzhou Center for Disease Control and Prevention, Guangzhou, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Department of Toxicology, Guangzhou Center for Disease Control and Prevention, Guangzhou, China.
authors.forename: Wenxue
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Thoracic Surgery, Cancer Center of Guangzhou Medical University, Guangzhou, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Guangzhou Key Laboratory of Environmental Health and Risk Assessment, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou, China.|Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
authors.forename: Xiumei
authors.initials: X
authors.lastname: Xing
authors.affiliation: Guangzhou Key Laboratory of Environmental Health and Risk Assessment, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou, China.|Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
authors.forename: Zhini
authors.initials: Z
authors.lastname: He
authors.affiliation: Guangzhou Key Laboratory of Environmental Health and Risk Assessment, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou, China.|Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
authors.forename: Shan
authors.initials: S
authors.lastname: Wang
authors.affiliation: Guangzhou Key Laboratory of Environmental Health and Risk Assessment, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou, China.|Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
authors.forename: Fangping
authors.initials: F
authors.lastname: Wang
authors.affiliation: Guangzhou Key Laboratory of Environmental Health and Risk Assessment, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou, China.|Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Ma
authors.affiliation: Guangzhou Key Laboratory of Environmental Health and Risk Assessment, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou, China.|Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Bai
authors.affiliation: Guangzhou Key Laboratory of Environmental Health and Risk Assessment, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou, China.|Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
authors.forename: Xiaowen
authors.initials: X
authors.lastname: Zeng
authors.affiliation: Guangzhou Key Laboratory of Environmental Health and Risk Assessment, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou, China.|Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: Guangzhou Key Laboratory of Environmental Health and Risk Assessment, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou, China.|Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Gao
authors.affiliation: Guangzhou Key Laboratory of Environmental Health and Risk Assessment, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou, China.|Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: Guangzhou Key Laboratory of Environmental Health and Risk Assessment, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou, China.|Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Guangzhou Key Laboratory of Environmental Health and Risk Assessment, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou, China.|Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
authors.forename: Liping
authors.initials: L
authors.lastname: Chen
authors.affiliation: Guangzhou Key Laboratory of Environmental Health and Risk Assessment, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou, China.|Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Chen
mesh_terms: D016604:Aflatoxin B1 / Q000633:toxicity; D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics*; D042822:Genomic Instability; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism; D008807:Mice, Inbred BALB C; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D002273:Carcinogens; D006657:Histones; D012694:Serine; D016604:Aflatoxin B1; D054648:Protein Phosphatase 2
keywords: DNA damage response genes; chemical carcinogen-induced cell transformation; p-H3S10; p-H3S28; protein phosphatase 2A