Fumonisin B1 Epigenetically Regulates PTEN Expression and Modulates DNA Damage Checkpoint Regulation in HepG2 Liver Cells

Abstract

Fumonisin B1 (FB1), a Fusarium-produced mycotoxin, is found in various foods and feeds. It is a well-known liver carcinogen in experimental animals; however, its role in genotoxicity is controversial. The current study investigated FB1-triggered changes in the epigenetic regulation of PTEN and determined its effect on DNA damage checkpoint regulation in human liver hepatoma G2 (HepG2) cells. Following treatment with FB1 (IC50: 200 µM; 24 h), the expression of miR-30c, KDM5B, PTEN, H3K4me3, PI3K, AKT, p-ser473-AKT, CHK1, and p-ser280-CHK1 was measured using qPCR and/or Western blot. H3K4me3 enrichment at the PTEN promoter region was assayed via a ChIP assay and DNA damage was determined using an ELISA. FB1 induced oxidative DNA damage. Total KDM5B expression was reduced, which subsequently increased the total H3K4me3 and the enrichment of H3K4me3 at PTEN promoters. Increased H3K4me3 induced an increase in PTEN transcript levels. However, miR-30c inhibited PTEN translation. Thus, PI3K/AKT signaling was activated, inhibiting CHK1 activity via phosphorylation of its serine 280 residue preventing the repair of damaged DNA. In conclusion, FB1 epigenetically modulates the PTEN/PI3K/AKT signaling cascade, preventing DNA damage checkpoint regulation, and induces significant DNA damage.

Research Progress on Fumonisin B1 Contamination and Toxicity: A Review

“…8-OH-DG is a biomarker of oxidative DNA damage, which induces DNA hypomethylation and thus affects cellular stability [ 64 ]. This result is identical to the study by Demirel et al and Arumugam et al [ 65 , 66 ]. In the experiments on rat liver epithelial cell line (Clone 9) and rat kidney proximal tubular epithelial cell line (NRK-52E), FB1 leads to methylation of tumor-related genes (p16, VHL, E-cadherin, and c-myc) [ 65 ].…”

“…In the experiments on rat liver epithelial cell line (Clone 9) and rat kidney proximal tubular epithelial cell line (NRK-52E), FB1 leads to methylation of tumor-related genes (p16, VHL, E-cadherin, and c-myc) [65]. Arumugam et al showed that, in HepG2 cells, FB1 suppressed the activity of checkpoint kinase 1 (CHK1) to generate DNA damage by regulating phosphatase and tensin homolog (PTEN), phosphoinositide 3-kinases (PI3K) and protein kinase B (Akt) [66]. This result is similar to that of Yu et al [67].…”

Effects of Chronic Exposure to Diets Containing Moldy Corn or Moldy Wheat Bran on Growth Performance, Ovarian Follicular Pool, and Oxidative Status of Gilts

“…Reddy et al (2008) showed that PTEN, a major negative regulator of phosphatidylinositol 3-kinase, is a critical regulator controlling oocyte growth and survival. In the present study, the expression levels of PTEN were elevated with increasing mycotoxin content in the diet, and there is evidence that mycotoxins such as FUM B1 [42], OA [43], and DON [44] can regulate PTEN signaling. Results of these studies suggest that mycotoxins might exert their negative effects on follicle survival via PTEN signaling.…”

Fumonisin B1 Inhibits Cell Proliferation and Decreases Barrier Function of Swine Umbilical Vein Endothelial Cells

“…[22]. It has speciesspecific toxicity that threatens the health of humans and animals [23]. Pulmonary edema is a unique pathological change due to the action of FB 1 in pigs [24].…”