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ToxSci Advance Access published online on May 28, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfg137
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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Received February 19, 2003; accepted April 24, 2003
© 2003 Society of Toxicology

Carcinogenicity

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

Jiuhong Kang 1*, Yuntao Zhang 1, Jie Chen 2, Haifeng Chen 3, Changjun Lin 1, Qin Wang 1, Yingxian Ou 2

1 School of Life Sciences, Lanzhou University, Lanzhou, Gansu 730000, China
2 Department of Hematology, General Hospital of Lanzhou, Gansu 730000, China
3 Institut de Topologie de Dynamique des Systemes, CNRS ESA 7986, Universite Paris7-Denis-Diderot,1, rue Guy de la Brosse, 75005 Paris, France

* To whom correspondence should be addressed. E-mail: kangjiuhong{at}lzu.edu.cn.


  Abstract

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 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. Co-administration 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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