Suppression of metallothionein-I/II expression and its probable molecular mechanisms.
Metallothionein (MT) promoter was methylated in rat hepatoma and in mouse lymphosarcoma cells by methylation of cytosine within the CpG dinucleotide region. After demethylation of MT-I promoter in mouse lymphosarcoma cells or in the transplanted rat hepatoma with 5-azacytidine, a potent inhibitor of DNA methyltransferase, the promoter was activated in response to heavy metal treatment. MT-I promoter was also suppressed in human prostate cancer lines PC3 and DU145, probably by promoter methylation, whereas cadmium induced MT-I in the human prostate cancer line LNCaP. In the prostate cancer lines where MT-I was suppressed, glutathione-S-transferase-pi (GST-pi) was expressed. On the contrary, GST-pi gene was repressed in the cell line where MT-I was induced, which suggests an inverse relationship between MT-I induction and GST-pi expression in some prostate cancer lines. The expressions of GST-pi and gamma-glutamyl cysteine synthase were also significantly higher (5- to 12-fold) in the lymphosarcoma cells and the hepatoma relative to the parental tissues. The higher expressions of these two genes suggest a compensatory mechanism in the cells where the gene for the antioxidant MT-I/II is not induced. MT-I/II may function as a growth suppressor either alone or in concert with other factor(s), and consequently their lack of expression could facilitate the tumor growth. In addition to suppression of MT-I/II expression by promoter methylation, the lack of MT induction could also be brought about by nuclear factor I (NFI), probably by interaction with the metal transcription factor MTF-1. An inverse relationship was observed between the level of NFI and MT-I expression in some cells, which suggests a role for NFI in the relatively low constitutive levels of MT-I expression in these cells.
Jacob
Samson T
ST
Department of Molecular and Cellular Biochemistry, College of Medicine, The Ohio State University, 333 Hamilton Hall, 1645 Neil Avenue, Columbus, OH 43210, USA. jacob.42@osu.edu
Majumder
Sarmila
S
Ghoshal
Kalpana
K
D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000096:biosynthesis; D006528:Carcinoma, Hepatocellular / Q000473:pathology / Q000662:veterinary; D003596:Cytosine / Q000378:metabolism; D004268:DNA-Binding Proteins; D015536:Down-Regulation; D006801:Humans; D008228:Lymphoma, Non-Hodgkin / Q000473:pathology / Q000662:veterinary; D008297:Male; D008668:Metallothionein / Q000096:biosynthesis*; D008745:Methylation; D051379:Mice; D051839:NFI Transcription Factors; D009687:Nuclear Proteins; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000473:pathology; D051381:Rats; D014157:Transcription Factors; D014407:Tumor Cells, Cultured; D051840:Y-Box-Binding Protein 1
D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D051839:NFI Transcription Factors; D009687:Nuclear Proteins; D014157:Transcription Factors; D051840:Y-Box-Binding Protein 1; C070856:YBX1 protein, human; D003596:Cytosine; D008668:Metallothionein