Arsenicals produce stable progressive changes in DNA methylation patterns that are linked to malignant transformation of immortalized urothelial cells

Abstract

Aberrant DNA methylation participates in carcinogenesis and is a molecular hallmark of a tumor cell. Tumor cells generally exhibit a redistribution of DNA methylation resulting in global hypomethylation with regional hypermethylation; however, the speed in which these changes emerge has not been fully elucidated and may depend on the temporal location of the cell in the path from normal, finite lifespan to malignant transformation. We used a model of arsenical-induced malignant transformation of immortalized human urothelial cells and DNA methylation microarrays to examine the extent and temporal nature of changes in DNA methylation that occur during the transition from immortal to malignantly transformed. Our data presented herein suggest that during arsenical-induced malignant transformation, aberrant DNA methylation occurs non-randomly, progresses gradually at hundreds of gene promoters, alters expression of the associated gene, and these changes are coincident with the acquisition of malignant properties, such as anchorage independent growth and tumor formation in immunocompromised mice. The DNA methylation changes appear stable, since malignantly transformed cells removed from the transforming arsenical exhibited no reversion in DNA methylation levels, associated gene expression, or malignant phenotype. These data suggest that arsenicals act as epimutagens and directly link their ability to induce malignant transformation to their actions on the epigenome.

The Redox Basis of Epigenetic Modifications: From Mechanisms to Functional Consequences

“…The Futscher group has been active in this field through a series of studies investigating exposure to arseniccontaining compounds. Their findings illustrate that arsenic promotes a broad, gradual, and lasting perturbation in DNA methylation patterns that contributes to arsenic-mediated carcinogenesis in urothelial cells (135,136,329). Collectively, these results strongly suggest that the direct perturbation of the iron loaded into epigenetic enzymes is a strong stimulus for the modification of cellular epigenetic status.…”

Intracellular Arsenic Speciation and Quantification in Human Urothelial and Hepatic Cells

“…Sam is known to transfer methyl groups to DNA methyltransferases on the one hand, and to AS3MT (arsenic (+3 oxidation state) methyltransferase) to the other hand (Ren et al, 2011). Jensen et al (2009) correlated the occurrence of aberrant DNA methylation patterns after chronic low-dose exposure to MMA(III) with the development of a malignant phenotype of UROtsa cells (Table 2.). …”

“…Inorganic arsenic and its metabolites are also known to be potent epigenetic modulators leading to (tissue specific) altered cellular functions, malignant transformation and tumorigenesis. Many studies report arsenic induced aberrant DNA methylation patterns (Sutherland & Costa, 2003;Smeester et al, 2011;Ren et al;, resulting in changes in the promoter activity that lead to altered gene expression (Jensen et al, 2009). Aberrant DNA methylation patterns might be the result of arsenic-induced altered global histone modification finally leading to, among others, the silencing of tumour suppressor genes (Zhou et al, 2008).…”

Epigenetics and its implications for ecotoxicology

“…Depressed levels of S-adenosyl-methionine were observed concurrently (Zhao et al 1997). In a recent study with immortalized human urothelial cells exposed to As, results from DNA methylation microarrays demonstrated non-random alterations in DNA methylation at multiple promoters and CpG rich sites in the genome (Jensen et al 2009). These aberrations were both hypo-and hypermethylation events.…”