Jacob Samson T, Majumder Sarmila, Ghoshal Kalpana
Department of Molecular and Cellular Biochemistry, College of Medicine, The Ohio State University, 333 Hamilton Hall, 1645 Neil Avenue, Columbus, OH 43210, USA.
Environ Health Perspect. 2002 Oct;110 Suppl 5(Suppl 5):827-30. doi: 10.1289/ehp.02110s5827.
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.
金属硫蛋白（MT）启动子在大鼠肝癌细胞和小鼠淋巴肉瘤细胞中，因CpG二核苷酸区域内胞嘧啶的甲基化而发生甲基化。在用DNA甲基转移酶的强效抑制剂5-氮杂胞苷对小鼠淋巴肉瘤细胞或移植的大鼠肝癌中的MT-I启动子进行去甲基化后，该启动子在重金属处理时被激活。MT-I启动子在人前列腺癌PC3和DU145细胞系中也受到抑制，可能是由于启动子甲基化，而镉可在人前列腺癌LNCaP细胞系中诱导MT-I的表达。在MT-I受到抑制的前列腺癌细胞系中，谷胱甘肽-S-转移酶-pi（GST-pi）表达。相反，在MT-I被诱导的细胞系中，GST-pi基因受到抑制，这表明在一些前列腺癌细胞系中MT-I诱导与GST-pi表达之间存在负相关关系。相对于亲代组织，淋巴肉瘤细胞和肝癌细胞中GST-pi和γ-谷氨酰半胱氨酸合成酶的表达也显著更高（5至12倍）。这两个基因的高表达表明在抗氧化剂MT-I/II基因未被诱导的细胞中存在一种补偿机制。MT-I/II可能单独或与其他因子协同发挥生长抑制作用，因此它们的表达缺失可能促进肿瘤生长。除了通过启动子甲基化抑制MT-I/II表达外，MT诱导的缺乏也可能由核因子I（NFI）引起，可能是通过与金属转录因子MTF-1相互作用。在一些细胞中观察到NFI水平与MT-I表达之间存在负相关关系，这表明NFI在这些细胞中MT-I相对较低的组成型表达水平中起作用。
