Nickel chloride regulates ANGPTL4 via the HIF-1α-mediated TET1 expression in lung cells. (1st November 2021)

• Record Type: Journal Article
• Authors: Kang, Yu-Ting; Li, Chien-Te; Tang, Sheau-Chung; Hsin, I-Lun; Lai, Yen-Chein; Hsiao, Yu-Ping; Ko, Jiunn-Liang
• Is Part Of: Toxicology letters. Volume 352(2021)
• Page Start: 17
• Page End: 25
• Publication Date: 2021-11-01
• Subjects: ANGPTL4 angiopoietin-like protein 4 -- HIF-1α hypoxia-inducible factor 1 α -- TCGA the Cancer Genome Atlas -- LUAD lung adenocarcinoma -- MSP methylation-specific PCR -- NiCl2 nickel chloride -- ROS reactive oxygen species -- TET1 Ten-eleven translocation 1; Nickel chloride -- Angiopoietin-like protein 4 -- Hypoxia-inducible factor 1 alpha -- Ten-eleven translocations -- Epigenetic regulation -- Hypomethylation; Toxicology -- Periodicals; 363.179
• DOI: 10.1016/j.toxlet.2021.09.007
• Languages: English
• ISSNs: 0378-4274

Abstract

Graphical abstract: Highlights: Nickel chloride treatment induces the expression of ANGPTL4 through HIF-1α/TET-1 activation in lung epithelial cells. Nickel chloride causes hypomethylation of ANGPTL4 promoter by TET-1 upregulation. The high ANGPTL4 and HIF-1α coexpression are correlated with poor survival outcomes for patients with LUAD. Abstract: Angiopoietin-like protein 4 (ANGPTL4) is a hypoxia-induced gene, and its high expression is associated with poor prognosis and promotion of tumour progression in several cancers. Some studies reported that ANGPTL4 is affected by epigenetic regulation. Our previous results demonstrated that ANGPTL4 is highly expressed in most lung cancer cell lines than in normal cell lines and is upregulated by HIF-1α accumulation under NiCl2 exposure. The accurate role of ANGPTL4 and its methylation status caused by nickel in the lung carcinogenesis is not fully explored yet. In this study, we found that ANGPTL4 and HIF-1α in lung adenocarcinoma (LUAD) tissues were significantly upregulated compared with those in normal tissues in The Cancer Genome Atlas (TCGA) cohort ( p < 0.001). The ANGPTL4 expression was statistically correlated to advanced stage ( p = 0.019) and N value (p = 0.002). The Kaplan–Meier analysis revealed that ANGPTL4 and HIF-1α expression levels were independently associated with the 5-year survival of patients with LUAD in TCGA database and immunohistochemistry staining. In vitro experiments indicated that ANGPTL4 was upregulated by the demethylation agent. The methylation-specific PCR and bisulfite sequencing assessed the methylation status of the ANGPTL4 promoter, and results showed that NiCl2 -treated cells had low ANGPTL4 methylation status. We further demonstrated that the DNA demethylase, TET1, was significantly increased under NiCl2 exposure. The knockdown of TET1 expression repressed the NiCl2 -induced ANGPTL4. We also showed that nickel-induced TET1 was stimulated by HIF-1α. Our work established ANGPTL4 as a potential oncogene that contributes to lung cancer progression and nickel-elicited carcinogenesis.