Fumonisin B1 alters global m6A RNA methylation and epigenetically regulates Keap1-Nrf2 signaling in human hepatoma (HepG2) cells - PubMed Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2021 Apr;95(4):1367-1378.
doi: 10.1007/s00204-021-02986-5. Epub 2021 Jan 26.

Fumonisin B1 alters global m6A RNA methylation and epigenetically regulates Keap1-Nrf2 signaling in human hepatoma (HepG2) cells

Thilona Arumugam  1 , Terisha Ghazi  1 , Anil A Chuturgoon  2
Affiliations

Fumonisin B1 alters global m6A RNA methylation and epigenetically regulates Keap1-Nrf2 signaling in human hepatoma (HepG2) cells

Thilona Arumugam et al. Arch Toxicol. 2021 Apr.

Abstract

FB1 is a common contaminant of cereal grains that affects human and animal health. It has become increasingly evident that epigenetic changes are implicated in FB1 toxicity. N6-methyladenosine (m6A), the most abundant post-transcriptional RNA modification, is influenced by fluctuations in redox status. Since oxidative stress is a characteristic of FB1 exposure, we determined if there is cross-talk between oxidative stress and m6A in FB1-exposed HepG2 cells. Briefly, HepG2 cells were treated with FB1 (0, 5, 50, 100, 200 µM; 24 h) and ROS, LDH and m6A levels were quantified. qPCR was used to determine the expression of m6A modulators, Nrf2, Keap1 and miR-27b, while western blotting was used to quantify Keap1 and Nrf2 protein expression. Methylation status of Keap1 and Nrf2 promoters was assessed and RNA immunoprecipitation quantified m6A-Keap1 and m6A-Nrf2 levels. FB1 induced accumulation of intracellular ROS (p ≤ 0.001) and LDH leakage (p ≤ 0.001). Elevated m6A levels (p ≤ 0.05) were accompanied by an increase in m6A "writers" [METLL3 (p ≤ 0.01) and METLL14 (p ≤ 0.01)], and "readers" [YTHDF1 (p ≤ 0.01), YTHDF2 (p ≤ 0.01), YTHDF3 (p ≤ 0.001) and YTHDC2 (p ≤ 0.01)] and a decrease in m6A "erasers" [ALKBH5 (p ≤ 0.001) and FTO (p ≤ 0.001)]. Hypermethylation and hypomethylation occurred at Keap1 (p ≤ 0.001) and Nrf2 (p ≤ 0.001) promoters, respectively. MiR-27b was reduced (p ≤ 0.001); however, m6A-Keap1 (p ≤ 0.05) and m6A-Nrf2 (p ≤ 0.01) levels were upregulated. This resulted in the ultimate decrease in Keap1 (p ≤ 0.001) and increase in Nrf2 (p ≤ 0.001) expression. Our findings reveal that m6A RNA methylation can be modified by exposure to FB1, and a cross-talk between m6A and redox regulators does occur.

Keywords: Epigenetics; Fumonisin B1; Keap1; Nrf2; Oxidative stress; m6A RNA methylation.

PubMed Disclaimer

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Agarwal V, Bell GW, Nam J-W, Bartel DP (2015) Predicting effective microRNA target sites in mammalian mRNAs. eLife 4:e05005. https://doi.org/10.7554/eLife.05005 - DOI - PMC
    1. Alizadeh AM et al (2012) Fumonisin B1 contamination of cereals and risk of esophageal cancer in a high risk area in northeastern Iran. Asian Pac J Cancer Prevent 13:2625–2628 - DOI
    1. Arumugam T, Pillay Y, Ghazi T, Nagiah S, Abdul NS, Chuturgoon AA (2019) Fumonisin B(1)-induced oxidative stress triggers Nrf2-mediated antioxidant response in human hepatocellular carcinoma (HepG2) cells. Mycotoxin Res 35:99–109. https://doi.org/10.1007/s12550-018-0335-0 - DOI - PubMed
    1. Arumugam T, Ghazi T, Chuturgoon A (2020) Fumonisin B 1 epigenetically regulates PTEN expression and modulates DNA damage checkpoint regulation in HepG2 liver cells. Toxins 12:2–15. https://doi.org/10.3390/toxins12100625 - DOI
    1. Barbano R et al (2013) Aberrant Keap1 methylation in breast cancer and association with clinicopathological features. Epigenetics 8:105–112 - DOI

Publication types

MeSH terms

LinkOut - more resources