Exposure to nickel chloride induces epigenetic modification on detoxification enzyme glutathione S-transferase M2.

Autor: Kang YT; Institute of Medicine, Chung-Shan Medical University, Taichung, Taiwan.; Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan., Yang WJ; Institute of Medicine, Chung-Shan Medical University, Taichung, Taiwan.; Department of Genomic Medicine, Changhua Christian Hospital, Changhua, Taiwan., Huang HC; Institute of Medicine, Chung-Shan Medical University, Taichung, Taiwan.; Division of Thoracic Surgery, Department of Surgery, Chung Shan Medical University Hospital, Taichung, Taiwan., Tang SC; Department of Nursing, National Taichung University of Science and Technology, Taichung, Taiwan., Ko JL; Institute of Medicine, Chung-Shan Medical University, Taichung, Taiwan.; Department of Medical Oncology and Chest Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan.
Jazyk: angličtina
Zdroj: Environmental toxicology [Environ Toxicol] 2024 Mar; Vol. 39 (3), pp. 1729-1736. Date of Electronic Publication: 2023 Dec 05.
DOI: 10.1002/tox.24055
Abstrakt: Nickel (Ni) is a human carcinogen with genotoxic and epigenotoxic effects. Environmental and occupational exposure to Ni increases the risk of cancer and chronic inflammatory diseases. Our previous findings indicate that Ni alters gene expression through epigenetic regulation, specifically impacting E-cadherin and angiopoietin-like 4 (ANGPTL4), involved in epithelial-mesenchymal transition and migration. GST-M2, a member of the glutathione S-transferase (GST) enzyme family, plays a crucial role in cellular defense against oxidative damage and has been increasingly associated with cancer. GST-M2 overexpression inhibits lung cancer invasion and metastasis in vitro and in vivo. Hypermethylation of its promoter in cancer cells reduces gene expression, correlating with poor prognosis in non-small-cell lung cancer patients. The impact of Ni on GST-M2 remains unclear. We will investigate whether nickel exerts regulatory effects on GST-M2 through epigenetic modifications. Additionally, metformin, an antidiabetic drug, is being studied as a chemopreventive agent against nickel-induced damage. Our findings indicate that nickel chloride (NiCl 2 ) exposure, both short-term and long-term, represses GST-M2 expression. However, the expression can be restored by demethylation agent 5-aza-2'-deoxycytidine and metformin. NiCl 2 promotes hypermethylation of the GST-M2 promoter, as confirmed by methylation-specific PCR and bisulfite sequencing. Additionally, NiCl 2 also influences histone acetylation, and metformin counteracts the suppressive effect of NiCl 2 on histone H3 expression. Metformin reestablishes the binding of specificity protein 1 to the GST-M2 promoter, which is otherwise disrupted by NiCl 2 . These findings elucidate the mechanism by which Ni reduces GST-M2 expression and transcriptional activity, potentially contributing to Ni-induced lung carcinogenesis.
(© 2023 Wiley Periodicals LLC.)
Databáze: MEDLINE
Externí odkaz: