Association of arsenic-induced malignant transformation with DNA hypomethylation and aberrant gene expression

Abstract

Inorganic arsenic, a human carcinogen, is enzymatically methylated for detoxication, consuming Sadenosyl-methionine (SAM) in the process. The fact that DNA methyltransferases (MeTases) require this same methyl donor suggests a role for methylation in arsenic carcinogenesis. Here we test the hypothesis that arsenic-induced initiation results from DNA hypomethylation caused by continuous methyl depletion. The hypothesis was tested by first inducing transformation in a rat liver epithelial cell line by chronic exposure to low levels of arsenic, as confirmed by the development of highly aggressive, malignant tumors after inoculation of cells into Nude mice. Global DNA hypomethylation occurred concurrently with malignant transformation and in the presence of depressed levels of S-adenosyl-methionine. Arsenic-induced DNA hypomethylation was a function of dose and exposure duration, and remained constant even after withdrawal of arsenic. Hyperexpressibility of the MT gene, a gene for which expression is clearly controlled by DNA methylation, was also detected in transformed cells. Acute arsenic or arsenic at nontransforming levels did not induce global hypomethylation of DNA. Whereas transcription of DNA MeTase was elevated, the MeTase enzymatic activity was reduced with arsenic transformation. Taken together, these results indicate arsenic can act as a carcinogen by inducing DNA hypomethylation, which in turn facilitates aberrant gene expression, and they constitute a tenable theory of mechanism in arsenic carcinogenesis.

MicroRNA Responses to Cellular Stress

“…Similar effects on alterations of genomic methylation status have also been reported for arsenic (23,34), which is metabolized for excretion through methylation and can thus alter the methyl-donor pool available in the cell. Our results show that the miRNAs of which the expression is specifically altered by arsenic exposure are those that are altered by folate deficiency, adding to the evidence that arsenic may operate by altering one-carbon metabolism and thus downstream epigenetic effects.…”

“…Arsenic exposure, like ionizing radiation and folate deficiency, has been linked to a variety of human cancers, including skin, bladder, and lung cancers (21). The mode of action of arsenic has been difficult to define due to its lack of carcinogenicity in animal models (22), but may be similar to folate deficiency, as arsenic may disrupt one-carbon metabolism and lead to diminished cellular genomic methylation (23). Because folate deficiency, arsenic exposure, and g-irradiation are all known developmental toxicants and human carcinogens, and as the fundamental understanding of the modes action of folate deficiency and arsenic exposure on initiation and development of cancer is incomplete, the fact that particular miRNA expression patterns are seen in both abnormal development and cancer led us to reason that the toxic effects mediated epigenetically by these exposures may be related to alteration in miRNA expression profiles.…”

Arsenic-induced malignant transformation of human keratinocytes: Involvement of Nrf2

“…Low-level, chronic arsenic exposure can induce malignant transformation in various human and rodent cells [28][29][30][31][32]. In the present study when HaCaT cells were continuously exposed to environmentally relevant levels of arsenic for a protracted period, malignant transformation occurred as evidenced by the formation of highly aggressive SCC, a common form of skin cancer in arsenic-exposed humans [1], after inoculation of nude mice.…”

Altered iron homeostasis involvement in arsenite-mediated cell transformation

“…Other studies show that arsenite is a complete transplacental carcinogen in mice [6], while dimethylarsinic acid, a major metabolite of arsenic in most mammals, including humans, causes bladder cancer in F344 rats [7]. In contrast to its weak mutagenicity, arsenite induces cell transformation of various types of cells to a more malignant phenotype, such as Syrian hamster embryo cells [8], mouse embryo fibroblasts [9], mouse epidermal JB6 C141 cells [10], rat liver-derived TRL 1215 cells [11], normal human immortalized prostate epithelium RWPE-1 cells [12], as well as human osteogenic sarcoma (HOS) cells [13,14]. Many mechanisms involving arsenic-mediated cell transformation have been proposed.…”

“…Many mechanisms involving arsenic-mediated cell transformation have been proposed. These include genomic instability [9], changes in cell signaling [10], and DNA hypomethylation [11,15]. Arsenite exposure was found to induce oxidative stress in cells [16][17][18].…”