Involvement of histone hypoacetylation in Ni2+-induced bcl- 2 down-regulation and human hepatoma cell apoptosis.
Although induction of cell apoptosis is known to be involved in the cytotoxicity of Ni(2+), little research has been aimed at the mechanism of Ni(2+)-induced apoptosis. Recent studies showed that Ni(2+) 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 Ni(2+)-induced apoptosis. To address this, effects of Ni(2+) on cell apoptosis, bcl- 2 gene expression and histone acetylation were examined in human hepatoma Hep3B cells. We found that Ni(2+) 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, Ni(2+) 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 Ni(2+)-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 Ni(2+). 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 Ni(2+)-induced cell apoptosis, where bcl- 2 is one of its targets.
Kang
Jiuhong
J
School of Life Sciences, Lanzhou University, 730000 Lanzhou, Gansu, China. kangjiuhong@lzu.edu.cn
Zhang
Dawei
D
Chen
Jie
J
Lin
Changjun
C
Liu
Qing
Q
D000107:Acetylation / Q000187:drug effects; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D006528:Carcinoma, Hepatocellular; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D019254:Genes, bcl-2 / Q000187:drug effects*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D009532:Nickel / Q000737:chemistry / Q000494:pharmacology*
D006657:Histones; D009532:Nickel