Reactive Oxygen-induced Carcinogenesis Causes Hypermethylation of p16Ink4a and Activation of MAP Kinase

Abstract

Background: Implantation of foreign materials into mice and humans has been noted to result in the appearance of soft tissue sarcomas at the site of implantation. These materials include metal replacement joints and Dacron vascular grafts. In addition, occupational exposure to nickel has been shown to result in an increased risk of carcinogenesis. The molecular mechanisms of foreign bodyinduced carcinogenesis are not fully understood. Materials and Methods: In order to gain insight into these mechanisms, we implanted nickel sulfide into wild type C57BL/6 mice as well as a mouse heterozygous for the tumor suppressor gene, p53.

Nickel Ions Inhibit Histone Demethylase JMJD1A and DNA Repair Enzyme ABH2 by Replacing the Ferrous Iron in the Catalytic Centers

“…By using a transgenic cell model with the target gene placed near heterochromatin, we were the first to demonstrate that nickel exposure caused a very high frequency of transgene silencing by increasing DNA methylation and repressive histone marks at the promoter of the silenced transgene (6 -8). In animal experiments, injection of particulate nickel compounds (nickel sulfide or nickel subsulfide) into mice induced formation of malignant fibrous histiocytomas and sarcomas, with the p16 and Fhit genes often found to be epigenetically silenced in these cancers (9,10). Additional studies have demonstrated that nickel exposure caused truncation of histone H2B and H2A as well as global alterations of a variety of histone modifications, such as histone acetylation, methylation, phosphorylation, and ubiquitination (11)(12)(13)(14)(15)(16)(17)(18)(19)(20).…”

Reactive oxygen signaling and MAPK activation distinguish Epstein–Barr Virus (EBV)-positive versus EBV-negative Burkitt's lymphoma

“…Based on prior results from our laboratory, we have demonstrated synergy between inactivation of p16ink4a and activation of mitogen-activated protein kinase (MAPK) (13)(14)(15). Also, we have found that cancers caused by reactive oxygen species (ROS) demonstrate high levels of hypermethylation of the tumor suppressor p16ink4a and activation of MAPK (16). Last, we have demonstrated that genes that generate reactive oxygen also activate angiogenesis and transform p16ink4a-deficient NIH 3T3 cells (17).…”

“…We hypothesized that MAPK is activated in tumors that are deficient in p16ink4a (11)(12)(13)(14)(15)(16). To test this hypothesis, we assessed the status of MAPK activation in BL cell lines.…”

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).…”