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Publication Detail

Title: Inhibition and reversal of nickel-induced transformation by the histone deacetylase inhibitor trichostatin A.

Authors: Zhang, Qunwei; Salnikow, Konstantin; Kluz, Thomas; Chen, Lung Chi; Su, Wei Cheng; Costa, Max

Published In Toxicol Appl Pharmacol, (2003 Nov 01)

Abstract: The carcinogenic process initiated by nongenotoxic carcinogens involves modulation of gene expression. Nickel compounds have low mutagenic activity, but are highly carcinogenic. In vitro both mouse and human cells can be efficiently transformed by soluble and insoluble nickel compounds to anchorage-independent growth. Because previous studies have shown that carcinogenic nickel compounds silence genes by inhibiting histone acetylation and enhancing DNA methylation, we investigated the effect of enhancing histone acetylation on cell transformation. The exposure of nickel-transformed cells to the histone deacetylase inhibitor trichostatin A (TSA) resulted in the appearance of significant number of revertants measured by their inability to grow in soft agar. Using the Affymetrix GeneChip we found that the level of expression of a significant number of genes was changed (suppressed or upregulated) in nickel-transformed clones but returned to a normal level in revertants obtained following TSA treatment. Moreover, we found that treatment of cells with TSA inhibited the ability of nickel to transform mouse PW cells to anchorage-independent growth. Treatment with TSA also inhibited the ability of nickel to transform human HOS cells, although to a lesser extent. In contrast, treatment with TSA was not able to revert established cancer cell lines as readily as the nickel-transformed cells. These data indicated that modulation of gene expression is important for nickel-induced transformation.

PubMed ID: 14575637 Exiting the NIEHS site

MeSH Terms: Animals; Anticarcinogenic Agents/pharmacology*; Cell Line, Tumor; Cell Transformation, Neoplastic/chemically induced; Cell Transformation, Neoplastic/drug effects*; Cell Transformation, Neoplastic/genetics; Dose-Response Relationship, Drug; Enzyme Inhibitors/pharmacology*; Gene Expression; Gene Expression Profiling; Gene Silencing; Histone Deacetylase Inhibitors*; Histone Deacetylases/genetics; Humans; Hydroxamic Acids/pharmacology*; Mice; Nickel/toxicity*; Oligonucleotide Array Sequence Analysis; Osteoblasts/drug effects; Osteoblasts/metabolism; Osteoblasts/pathology; RNA, Messenger/metabolism; Reverse Transcriptase Polymerase Chain Reaction

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