title: Suppression of metallothionein-I/II expression and its probable molecular mechanisms.
abstract: 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.
authors.affiliation: 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
authors.forename: Samson T
authors.initials: ST
authors.lastname: Jacob
authors.forename: Sarmila
authors.initials: S
authors.lastname: Majumder
authors.forename: Kalpana
authors.initials: K
authors.lastname: Ghoshal
mesh_terms: 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
chemical_list: 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