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Involvement of histone hypoacetylation in Ni2+-induced bcl-2 down-regulation and human hepatoma cell apoptosis

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Abstract

Although induction of cell apoptosis is known to be involved in the cytotoxicity of Ni2+, little research has been aimed at the mechanism of Ni2+-induced apoptosis. Recent studies showed that Ni2+ induces histone hypoacetylation in different cell lines. Since histone hypoacetylation plays important roles in the control of cell cycle progress and apoptosis, we hypothesized that histone hypoacetylation may be an unrevealed pathway in Ni2+-induced apoptosis. To address this, effects of Ni2+ on cell apoptosis, bcl-2 gene expression and histone acetylation were examined in human hepatoma Hep3B cells. We found that Ni2+ treatment resulted in cell proliferation arrest, the appearance of detached cells, condensed chromatin, apoptotic bodies and specific DNA fragmentation, indicating the occurrence of cell apoptosis. At the same time, Ni2+ induced a significant decrease in bcl-2 expression and histone acetylation; the decrease of histone H4 acetylation in nucleosomes associated with the bcl-2 promoter region was also proven by a chromatin immunoprecipitation assay, indicating the involvement of histone hypoacetylation in Ni2+-induced bcl-2 down-regulation. Further studies showed that increasing histone acetylation by either 100 nM of trichostatin A or over-expressing histone acetyltranferase p300 in Hep3B cells obviously attenuated the bcl-2 down-regulation and cell apoptosis caused by Ni2+. Considering the importance of bcl-2 in determining cell survival and apoptosis, the data presented here suggest that histone hypoacetylation may represent one unrevealed pathway in Ni2+-induced cell apoptosis, where bcl-2 is one of its targets.

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Fig. 1A, B
Fig. 2A–H
Fig. 3A, B
Fig. 4A–C
Fig. 5A–F
Fig. 6A–F

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Abbreviations

AB:

apoptotic body

ChIP:

chromatin immunoprecipitation

DAPI:

4’,6-diamidino-2-phenylindole

HAT:

histone acetyltransferase

HDAC:

histone deacetylase

MTT:

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

ROS:

reactive oxygen species

RT-PCR:

reverse transcription polymerase chain reaction

TSA:

trichostatin A

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Authors and Affiliations

  1. School of Life Sciences, Lanzhou University, 730000, Lanzhou, Gansu , China

    Jiuhong Kang, Dawei Zhang, Changjun Lin & Qing Liu

  2. Department of Hematology, General Hospital of Lanzhou, 730000, Lanzhou , China

    Jie Chen

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  1. Jiuhong Kang
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  2. Dawei Zhang
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  4. Changjun Lin
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Correspondence to Jiuhong Kang.

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Kang, J., Zhang, D., Chen, J. et al. Involvement of histone hypoacetylation in Ni2+-induced bcl-2 down-regulation and human hepatoma cell apoptosis. J Biol Inorg Chem 9, 713–723 (2004). https://doi.org/10.1007/s00775-004-0561-0

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