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.

Gene Expression Profiling of Intrahepatic Cholangiocarcinoma

“…In human liver tissues, MTs are expressed at high levels, whereas there is no MT expression in hepatocellular carcinomas. Down-regulation of MT genes can be caused by hypermethylation of MT promoter and by mutations in other genes, such as p53 tumor suppressor gene (Jacob et al, 2002). In this study, the Exon 1.0 ST microarray set was designed to capture the 14 major genes in MT pathway, and among these 14 genes, 9 were identified having significant changes in expression in ICC samples, namely, one up-regulated gene (FLNC) and 7 down-regulated genes of MT1 isoforms (MT1/ MT2A, MT1X,MT1H/MT1P2,MT1E|MT1M/MT1JP,MT1IP/MT1X,MT1H/MT1F,MT1G and HNF4A).…”

DNA methylation profile of 28 potential marker loci in malignant mesothelioma

“…The biological role of silencing of these metal-binding proteins in cancer remains to be further investigated. It has been suggested that MT expression might retard growth of cancer cells, or that lack of metallothioneins could increase availability of cellular zinc for cell growth [53].…”

Hypersusceptibility to cisplatin carcinogenicity in metallothionein‐I/II double knockout mice: Production of hepatocellular carcinoma at clinically relevant doses

“…[25][26][27][28] MT gene expression seems to be controlled, in part, by promoter region methylation, and different levels of methylation will result in altered expression. 31,32 It is also suspected that polymorphisms in the metalloregulatory transcription factor involved with control of the MT gene (MTF-1) might result in different expression-based phenotypes. 33 Whatever the basis of the large inter-individual variation in human MT expression, our results indicate that this variability might well impact the carcinogenic potential of cisplatin after chemotherapy.…”