Journal Article

Nickel-Induced Histone Hypoacetylation: The Role of Reactive Oxygen Species

Jiuhong Kang, Yuntao Zhang, Jie Chen, Haifeng Chen, Changjun Lin, Qin Wang and Yingxian Ou

in Toxicological Sciences

Volume 74, issue 2, pages 279-286
Published in print August 2003 | ISSN: 1096-6080
Published online August 2003 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/kfg137
Nickel-Induced Histone Hypoacetylation: The Role of Reactive Oxygen Species

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The carcinogenicity of specific insoluble nickel compounds is mainly due to their intracellular generation of Ni2+ ion and its suppression on gene transcription, while the inhibition of Ni2+ on histone acetylation plays an important role in the suppression or silencing of genes. Recent studies on Ni2+ and histone H4 acetylation suggest that Ni2+ inhibits the acetylation of histone H4 through binding with its N-terminal histidine-18. It is well known that bound Ni2+ readily produces reactive oxygen species (ROS) in vivo, a critical factor inversely related with the occurrence of resistance of mammalian cells to Ni2+. Thus, we tried to find the possible role of ROS in the induction of Ni2+ on histone acetylation in the present study. We found that a high concentration of Ni2+ (no less than 600 μM) caused a significant decrease of histone acetylation in human hepatoma cells. This inhibition was shown to result mainly from the influence of Ni2+ on the overall histone acetyltransferase (HAT) activity indicated by the histone acetylation assay with the presence of a specific histone deacetylase (HDAC) inhibitor, trichostatin A (TSA). The in vitro HAT and HDAC assays further confirmed this result. At the same time, we found that the exposure of hepatoma cells to Ni2+ generated ROS. Coadministration of hydrogen peroxide with Ni2+ generated more ROS and more histone acetylation inhibition. Addition of the antioxidants 2-mercaptoethanol (2-ME) at 2 mM or N-acetyl-cysteine (NAC) at 1 mM, with Ni2+ together, completely suppressed ROS generation and significantly diminished the induced histone hypoacetylation. The data presented here prove that the ROS generation plays a role in the inhibition of histone acetylation, and, hence, the gene suppression and carcinogenesis caused by Ni2+ exposure, providing a new door for us to continuously understand the mechanism of ROS in the carcinogenicity of Ni2+ and the resistance of mammalian cells to Ni2+.

Keywords: Nickel; carcinogenesis; histone acetylation; histone acetyltransferase (HAT); histone deacetylase (HDAC); reactive oxygen species (ROS)

Journal Article.  5112 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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