title: Histone Deacetylase Inhibitors Trichostatin A and MCP30 Relieve Benzene-Induced Hematotoxicity via Restoring Topoisomerase IIα.
abstract: Dysfunction of histone acetylation inhibits topoisomerase IIα (Topo IIα), which is implicated in benzene-induced hematotoxicity in patients with chronic benzene exposure. Whether histone deacetylase (HDAC) inhibitors can relieve benzene-induced hematotoxicity remains unclear. Here we showed that hydroquinone, a main metabolite of benzene, increased the HDAC activity, decreased the Topo IIα expression and induced apoptosis in human bone marrow mononuclear cells in vitro, and treatment with two HDAC inhibitors, namely trichostatin A (TSA) or a mixture of ribosome-inactivating proteins MCP30, almost completely reversed these effects. We further established a benzene poisoning murine model by inhaling benzene vapor in a container and found that benzene poisoning decreased the expression and activity of Topo IIα, and impaired acetylation of histone H4 and H3. The analysis of regulatory factors of Topo IIα promoter found that benzene poisoning decreased the mRNA levels of SP1 and C-MYB, and increased the mRNA level of SP3. Both TSA and MCP30 significantly enhanced the acetylation of histone H3 and H4 in Topo IIα promoter and increased the expression and activity of Topo IIα in benzene poisoning mice, which contributed to relieve the symptoms of hematotoxicity. Thus, treatment with HDAC inhibitors represents an attractive approach to reduce benzene-induced hematotoxicity.
authors.affiliation: Department of Hematology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325015, China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Hematology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325015, China.
authors.forename: Zhouyi
authors.initials: Z
authors.lastname: Zheng
authors.affiliation: Department of Hematology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325015, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Hematology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325015, China.
authors.forename: Jiaqi
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Hematology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325015, China.
authors.forename: Shanhu
authors.initials: S
authors.lastname: Qian
authors.affiliation: Department of Hematology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325015, China.
authors.forename: Yifen
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Department of Hematology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325015, China.
authors.forename: Lan
authors.initials: L
authors.lastname: Sun
authors.affiliation: Laboratory of Internal Medicine, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325015, China.
authors.forename: Yixiang
authors.initials: Y
authors.lastname: Han
authors.affiliation: Department of Hematology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325015, China.
authors.forename: Shenghui
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Hematology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325015, China.
authors.forename: Kang
authors.initials: K
authors.lastname: Yu
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D001554:Benzene / Q000633:toxicity*; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D003521:Cyclopropanes / Q000494:pharmacology*; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008297:Male; D051379:Mice; D011401:Promoter Regions, Genetic / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; D003521:Cyclopropanes; D004268:DNA-Binding Proteins; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D012333:RNA, Messenger; C012589:trichostatin A; D006655:Histone Deacetylases; D004250:DNA Topoisomerases, Type II; D001554:Benzene; C412563:1-methylcyclopropene