Xia Bo, Yang Lin-Qing, Huang Hai-Yan, Pang Li, Yang Xi-Fei, Yi You-Jin, Ren Xiao-Hu, Li Jie, Zhuang Zhi-Xiong, Liu Jian-Jun
Key Laboratory of Modern Toxicology, Shenzhen Center for Disease Control and Prevention, Shenzhen, China College of Food Science and Technology, Hunan Agricultural University, Changsha, Hunan, China.
Key Laboratory of Modern Toxicology, Shenzhen Center for Disease Control and Prevention, Shenzhen, China.
Int J Toxicol. 2016 May;35(3):336-43. doi: 10.1177/1091581816637071. Epub 2016 Mar 8.
Benzo[a]pyrene (B[a]P) exposure has been associated with the alteration in epigenetic marks that are involved in cancer development. Biotinidase (BTD) and holocarboxylase synthetase (HCS) are 2 major enzymes involved in maintaining the homeostasis of biotinylation, and the deregulation of this pathway has been associated with a number of cancers. However, the link between B[a]P exposure and the dysregulation of BTD/HCS in B[a]P-associated tumorigenesis is unknown. Here we showed that the expression of both BTD and HCS was significantly decreased upon B[a]P treatment in human bronchial epithelial (16HBE) cells. Benzo[a]pyrene exposure led to the global loss of DNA methylation by immunofluorescence, which coincided with the reduction in acetylation levels on histones H3 and H4 in 16HBE cells. Consistent with decreased histone acetylation, histone deacetylases (HDACs) HDAC2 and HDAC3 were significantly upregulated in a dosage-dependent manner. When DNA methylation or HDAC activity was inhibited, we found that the reduction in BTD and HCS was separately regulated through distinct epigenetic mechanisms. Together, our results suggested the potential link between B[a]P toxicity and deregulation of biotin homeostasis pathway in B[a]P-associated cancer development.
苯并[a]芘（B[a]P）暴露与参与癌症发展的表观遗传标记改变有关。生物素酶（BTD）和全羧化酶合成酶（HCS）是参与维持生物素化稳态的两种主要酶，该途径的失调与多种癌症有关。然而，B[a]P暴露与B[a]P相关肿瘤发生中BTD/HCS失调之间的联系尚不清楚。在此我们表明，在人支气管上皮（16HBE）细胞中用B[a]P处理后，BTD和HCS的表达均显著降低。苯并[a]芘暴露通过免疫荧光导致DNA甲基化的整体丧失，这与16HBE细胞中组蛋白H3和H4乙酰化水平的降低相一致。与组蛋白乙酰化降低一致，组蛋白脱乙酰酶（HDAC）HDAC2和HDAC3以剂量依赖性方式显著上调。当DNA甲基化或HDAC活性受到抑制时，我们发现BTD和HCS的降低是通过不同的表观遗传机制分别调节的。总之，我们的结果表明了B[a]P毒性与B[a]P相关癌症发展中生物素稳态途径失调之间的潜在联系。
