title: Hypomethylation mediated by decreased DNMTs involves in the activation of proto-oncogene MPL in TK6 cells treated with hydroquinone.
abstract: Hydroquinone (HQ), one of the most important metabolites derived from benzene, is known to be associated with acute myelogenous leukemia (AML) risk, however, its carcinogenic mechanism remains unclear. In this study, the epigenetic mechanism of HQ exposure was investigated. We characterized the epigenomic response of TK6 cells to HQ exposure, and examined the mRNA expression of DNA methyltransferases (DNMTs) including DNMT1, DNMT3a and DNMT3b, methyl-CpG-binding domain protein 2 (MBD2) and six proto-oncogenes (MPL, RAF1, MYB, MYC, ERBB2 and BRAF). Compared to the control cells, HQ exposure (2.5, 5.0, 10.0 and 20.0 μM for 48 h) resulted in the decrease of DNMTs and MBD2 expression, the global hypomethylation and increase of MPL at mRNA level. Meanwhile, most of these changes were in dose-dependent manner. Moreover, inhibition of DNMTs induced by 5-aza-2'-deoxycytidine (5-AZA), an identified DNMT inhibitor, caused more induction of MPL expression at mRNA level compared to the HQ (10.0 μM) pre-treated group. Furthermore, treatment of HQ potentially led to MPL itself hypomethylation (10.0 and 20.0 μM reduced by 47% and 44%, respectively), further revealing that the activation of proto-oncogene MPL was related to hypomethylation in its DNA sequences. In conclusion, hypomethylation, including global and specific hypomethylation, might be involved in the activation of MPL, and the hypomethylation could be induced by decreased DNMTs in TK6 cells exposed to HQ.
authors.affiliation: Department of Environmental and Occupational Health, School of Public Health, Guangdong Medical College, Dongguan 523808, PR China.
authors.forename: Linhua
authors.initials: L
authors.lastname: Liu
authors.forename: Xiaoxuan
authors.initials: X
authors.lastname: Ling
authors.forename: Hairong
authors.initials: H
authors.lastname: Liang
authors.forename: Yuting
authors.initials: Y
authors.lastname: Gao
authors.forename: Hui
authors.initials: H
authors.lastname: Yang
authors.forename: Junli
authors.initials: J
authors.lastname: Shao
authors.forename: Huanwen
authors.initials: H
authors.lastname: Tang
mesh_terms: D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000096:biosynthesis*; D019175:DNA Methylation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000633:toxicity*; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D006873:Hydroquinones / Q000633:toxicity*; D020084:Long Interspersed Nucleotide Elements / Q000235:genetics; D000090063:Proto-Oncogene Mas; D060888:Real-Time Polymerase Chain Reaction; D053628:Receptors, Thrombopoietin / Q000235:genetics*
chemical_list: D004785:Environmental Pollutants; D006873:Hydroquinones; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D053628:Receptors, Thrombopoietin; C082218:MPL protein, human; D004248:DNA (Cytosine-5-)-Methyltransferases; C031927:hydroquinone