Ge Yichen, Zhu Jinqiu, Wang Xue, Zheng Nina, Tu Chengjian, Qu Jun, Ren Xuefeng
Department of Epidemiology and Environmental Health, School of Public Health and Health Professions, The State University of New York, Buffalo, NY 14214, USA.
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, The State University of New York, Buffalo, NY 14214, USA.
Toxicol Appl Pharmacol. 2018 Sep 15;355:164-173. doi: 10.1016/j.taap.2018.06.029. Epub 2018 Jun 30.
Arsenic is a known potent risk factor for bladder cancer. Increasing evidence suggests that epigenetic alterations, e.g., DNA methylation and histones posttranslational modifications (PTMs), contribute to arsenic carcinogenesis. Our previous studies have demonstrated that exposure of human urothelial cells (UROtsa cells) to monomethylarsonous acid (MMA), one of arsenic active metabolites, changes the histone acetylation marks across the genome that are correlated with MMA-induced UROtsa cell malignant transformation. In the current study, we employed a high-resolution and high-throughput liquid chromatography tandem mass spectrometry (LC-MS/MS) to identify and quantitatively measure various PTM patterns during the MMA-induced malignant transformation. Our data showed that MMA exposure caused a time-dependent increase in histone H3 acetylation on lysine K4, K9, K14, K18, K23, and K27, but a decrease in acetylation on lysine K5, K8, K12, and K16 of histone H4. Consistent with this observation, H3K18ac was increased while H4K8ac was decreased in the leukocytes collected from people exposed to high concentrations of arsenic compared to those exposed to low concentrations. MMA was also able to alter histone methylation patterns: MMA transformed cells experienced a loss of H3K4me1, and an increase in H3K9me1 and H3K27me1. Collectively, our data shows that arsenic exposure causes dynamic changes in histone acetylation and methylation patterns during arsenic-induced cancer development. Exploring the genomic location of the altered histone marks and the resulting aberrant expression of genes will be of importance in deciphering the mechanism of arsenic-induced carcinogenesis.
砷是已知的膀胱癌强效风险因素。越来越多的证据表明，表观遗传改变，如DNA甲基化和组蛋白翻译后修饰（PTM），在砷致癌过程中起作用。我们之前的研究表明，将人尿路上皮细胞（UROtsa细胞）暴露于砷的活性代谢产物之一单甲基亚胂酸（MMA），会改变全基因组的组蛋白乙酰化标记，这与MMA诱导的UROtsa细胞恶性转化相关。在本研究中，我们采用高分辨率和高通量液相色谱串联质谱（LC-MS/MS）来鉴定和定量测量MMA诱导的恶性转化过程中的各种PTM模式。我们的数据表明，MMA暴露导致组蛋白H3赖氨酸K4、K9、K14、K18、K23和K27位点的乙酰化随时间增加，但组蛋白H4赖氨酸K5、K8、K12和K16位点的乙酰化减少。与这一观察结果一致，与低浓度砷暴露人群相比，高浓度砷暴露人群白细胞中的H3K18ac增加而H4K8ac减少。MMA还能够改变组蛋白甲基化模式：MMA转化的细胞经历了H3K4me1的丢失以及H3K9me1和H3K27me1的增加。总的来说，我们的数据表明，砷暴露在砷诱导的癌症发展过程中会导致组蛋白乙酰化和甲基化模式的动态变化。探索组蛋白标记改变的基因组位置以及由此导致的基因异常表达对于解读砷诱导致癌的机制具有重要意义。
