DNA Hypermethylation of Promoter of Gene p53 and p16 in Arsenic-Exposed People with and without Malignancy

Abstract

Chronic arsenic exposure is known to produce arsenicosis and cancer. To ascertain whether perturbation of methylation plays a role in such carcinogenesis, the degree of methylation of p53 and p16 gene in DNA obtained from blood samples of people chronically exposed to arsenic and skin cancer subjects was studied. Methylation-specific restriction endonuclease digestion followed by polymerase chain reaction (PCR) of gene p53 and bisulfite treatment followed by methylation-sensitive PCR of gene p16 have been carried out to analyze the methylation status of the samples studied. Significant DNA hypermethylation of promoter region of p53 gene was observed in DNA of arsenic-exposed people compared to control subjects. This hypermethylation showed a dose-response relationship. Further, hypermethylation of p53 gene was also observed in arsenic-induced skin cancer patients compared to subjects having skin cancer unrelated to arsenic, though not at significant level. However, a small subgroup of cases showed hypomethylation with high arsenic exposure. Significant hypermethylation of gene p16 was also observed in cases of arsenicosis exposed to high level of arsenic. In man, arsenic has the ability to alter DNA methylation patterns in gene p53 and p16, which are important in carcinogenesis.

Neoplastic Transformation of Human Small Airway Epithelial Cells Induced by Arsenic

“…Some reports demonstrated that arsenic could induce p53 accumulation in an ATM-dependent pathway (44); the overexpressed p53 was a mutant form, and most frequent mutation sites were found in exons 5 and 8, so mutated p53 subsequently led to its normal function loss. Other studies (45)(46)(47) documented that the promoter of p53 in arsenic-exposed cells exhibited hypermethylation as some carcinoma appeared; consequently, p53 expression decreased, resulting in its function loss or partial loss, so the cells were predisposed to uncontrolled proliferation, genomic instability, or apoptosis. In our study, p53 did not show mutations in its coding region upon chronic arsenic treatment, yet its protein expression was remarkably decreased relative to the control cells.…”

DNA methylation in white blood cells

“…Arsenic has been associated with gene-specific hypermethylation of p53 and p16 promoter regions in blood DNA of subjects exposed to toxic level of arsenic compared to controls. 60 Hypermethylation of the p16 promoter was also observed in WBC DNA from 103 patients with arseniasis compared to 110 healthy subjects. 61 Air pollution.…”

LINE-1 gene hypomethylation and p16 gene hypermethylation in HepG2 cells induced by low-dose and long-term triclosan exposure: The role of hydroxyl group

“…And the data of low-dose TCS exposure on ESR1 gene methylation levels suggests that the p16 gene hypermethylation may be the gene-special change in TCS exposed HepG2 cell. Actually, some environmental chemicals can induce p16 gene hypermethylation, such as particulate matter 2.5 (Soberanes et al, 2012), arsenic (Chanda et al, 2006;Zhang et al, 2007), nickel (Govindarajan et al, 2002), HCB, TCDD (Ozden et al, 2015), and chromium (Kondo et al, 2006).…”