title: Inhibition of monomethylarsonous acid (MMA(III))-induced cell malignant transformation through restoring dysregulated histone acetylation.
abstract: Inorganic arsenic (iAs) and its high toxic metabolite, monomethylarsonous acid (MMA(III)), are able to induce malignant transformation of human cells. Chronic exposure to these chemicals is associated with an increased risk of developing multiple cancers in human. However, the mechanisms contributing to iAs/MMA(III)-induced cell malignant transformation and carcinogenesis are not fully elucidated. We recently showed that iAs/MMA(III) exposure to human cells led to a decreased level of histone acetylation globally, which was associated with an increased sensitivity to arsenic cytotoxicity. In the current study, it demonstrated that prolonged exposure to low-level MMA(III) in human urothelial cells significantly increased the expression and activity of histone deacetylases (HDACs) with an associated reduction of histone acetylation levels both globally and lysine specifically. Administration of the HDAC inhibitor, suberoylanilide hydroxamic acid (SAHA), at 4 weeks after the initial MMA(III) treatment inhibited the MMA(III)-mediated up-regulation of the expression and activities of HDACs, leading to increase histone acetylation and prevention of MMA(III)-induced malignant transformation. These new findings suggest that histone acetylation dysregulation may be a key mechanism in MMA(III)-induced malignant transformation and carcinogenesis, and that HDAC inhibitors could be targeted to prevent or treat iAs-related cancers.
authors.affiliation: The Key Laboratory of Gene Engineering of Education Ministry, Sun Yat-sen University, Guangzhou 510275, PR China; Department of Social and Preventive Medicine, School of Public Health and Health Professions, The State University of New York, Buffalo, NY 14214, USA; Guangdong Provincial Key Laboratory of Occupational Disease Prevention and Treatment, Guangdong Prevention and Treatment Center for Occupational Diseases, Guangzhou 510300, PR China.
authors.forename: Yichen
authors.initials: Y
authors.lastname: Ge
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Gong
authors.forename: James R
authors.initials: JR
authors.lastname: Olson
authors.forename: Peilin
authors.initials: P
authors.lastname: Xu
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Buck
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Ren
mesh_terms: D000107:Acetylation; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced*; D002478:Cells, Cultured; D056284:Histone Deacetylase 1 / Q000235:genetics; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006657:Histones / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D009942:Organometallic Compounds / Q000633:toxicity*; D000077337:Vorinostat
chemical_list: D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D009942:Organometallic Compounds; C406082:monomethylarsonous acid; D000077337:Vorinostat; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1
keywords: Arsenic; Cell malignant transformation; HATs; HDAC inhibitor; HDACs; Histone acetylation; MMA(III); Monomethylarsonous acid (MMA(III)); SAHA; histone acetyltransferases; histone deacetylases; iAs; inorganic arsenic; monomethylarsonous acid; suberoylanilide hydroxamic acid