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.
Toxicology. 2013 Oct 4;312:30-5. doi: 10.1016/j.tox.2013.07.011. Epub 2013 Jul 26.
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.
无机砷 (iAs) 及其高毒性代谢物一甲基砷酸 (MMA(III)) 能够诱导人细胞恶性转化。慢性暴露于这些化学物质会增加人类多种癌症的发病风险。然而，导致 iAs/MMA(III)诱导细胞恶性转化和致癌的机制尚未完全阐明。我们最近表明，iAs/MMA(III)暴露于人细胞会导致组蛋白乙酰化水平整体降低，这与砷细胞毒性敏感性增加有关。在本研究中，我们证明了在人尿路上皮细胞中长时间暴露于低水平的 MMA(III) 会显著增加组蛋白去乙酰化酶 (HDACs) 的表达和活性，从而导致组蛋白乙酰化水平在整体和赖氨酸特异性上降低。在初始 MMA(III) 处理 4 周后，给予组蛋白去乙酰化酶抑制剂（SAHA）可抑制 MMA(III)介导的 HDACs 表达和活性的上调，导致组蛋白乙酰化增加，并预防 MMA(III)诱导的恶性转化。这些新发现表明，组蛋白乙酰化失调可能是 MMA(III)诱导的恶性转化和致癌的关键机制，组蛋白去乙酰化酶抑制剂可能成为预防或治疗 iAs 相关癌症的靶点。
