Basic mechanics of DNA methylation and the unique landscape of the DNA methylome in metal-induced carcinogenesis

Abstract

DNA methylation plays an intricate role in the regulation of gene expression and events that compromise the integrity of the methylome may potentially contribute to disease development. DNA methylation is a reversible and regulatory modification that elicits a cascade of events leading to chromatin condensation and gene silencing. In general, normal cells are characterized by gene-specific hypomethylation and global hypermethylation, while cancer cells portray a reverse profile to this norm. The unique methylome displayed in cancer cells is induced after exposure to carcinogenic metals such as nickel, arsenic, cadmium, and chromium (VI). These metals alter the DNA methylation profile by provoking both hyper- and hypomethylation events. The metal-stimulated deviations to the methylome are possible mechanisms for metal-induced carcinogenesis and may provide potential biomarkers for cancer detection. Development of therapies based on the cancer methylome requires further research including human studies that supply results with larger impact and higher human relevance.

Arsenic Induces Polyadenylation of Canonical Histone mRNA by Down-regulating Stem-Loop-binding Protein Gene Expression

“…To test the possibility, we used Northern blotting to measure the percentage of polyadenylated H3.1 mRNA in total H3.1 mRNA before and after arsenic exposure. BEAS-2B cells were utilized because of the known association of arsenic exposure and lung cancer (44) as well as the ability of this cell line to undergo malignant transformation after metal exposure (21,22,27,45). Poly(A) ϩ mRNAs were purified from total RNA using poly(dT) beads, and the unbound fraction was designated as the poly(A) Ϫ fraction.…”

“…Arsenic has been demonstrated to silence genes by increasing DNA methylation and altering histone modifications at the promoter of genes (21,22). The mechanisms underlying arsenic-induced epigenetic alterations are vague, but various investigations have reported on the effect of arsenic on a number of epigenetic enzymes, such as EZH2 (23,24) and G9a (25).…”

Chromatin Memory in the Development of Human Cancers

“…DNA methylation is a kind of modification that a methyl group is added covalently to 5-position of the cytosine [10]. The modified DNA bases act as regulatory marks that regulate gene expression in concert with their genomic location and density.…”

“…Newly synthesized DNA is methylated by DNMT1 by its binding to hemimethylated DNA during DNA replication and copying 5mC marks from the parental strand to the newly synthesized strand [10]. DNMT3A and DNMT3B are de novo methyltransferases establishing 5mC patterns in germ cells and developing embryos.…”

“…This review focuses on chromatin remodeling and the associated histone modifiers in the development of cancer, the application of these modifiers as a cancer therapy target in different clinical trial phases is also discussed. For interests in other epigenetic aspects, extensive reviews can be found in area of LINE-1 methylation patterns in cancer cells [9], DNA methylation and the unique landscape of the DNA methylome in cancer [10,11], and alterations of non-coding RNAs in cancers [12].…”