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ToxSci Advance Access originally published online on May 28, 2003
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Toxicological Sciences 74, 279-286 (2003)
Copyright © 2003 by the Society of Toxicology

CARCINOGENICITY

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

Jiuhong Kang*,1, Yuntao Zhang*, Jie Chen{dagger}, Haifeng Chen{ddagger}, Changjun Lin*, Qin Wang* and Yingxian Ou{dagger}

* School of Life Sciences, Lanzhou University, Lanzhou, Gansu 730000, China; {dagger} Department of Hematology, General Hospital of Lanzhou, Gansu 730000, China; and {ddagger} Institut de Topologie de Dynamique des Systemes, CNRS ESA 7986, Université Paris 7-Denis-Diderot, 1 Rue Guy de la Brosse, 75005 Paris, France

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+.

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


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