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Fusaric acid decreases p53 expression by altering promoter methylation and m6A RNA methylation in human hepatocellular carcinoma (HepG2) cells.

ABSTRACT: Fusaric acid (FA) is a food-borne mycotoxin that mediates toxicity with limited information on its epigenetic properties. p53 is a tumour suppressor protein that regulates cell cycle arrest and apoptotic cell death. The expression of p53 is regulated transcriptionally by promoter methylation and post-transcriptionally by N-6-methyladenosine (m6A) RNA methylation. We investigated the effect of FA on p53 expression and its epigenetic regulation via promoter methylation and m6A RNA methylation in human hepatocellular carcinoma (HepG2) cells. HepG2 cells were treated with FA [0, 25, 50, 104, and 150 µg/ml; 24 h] and thereafter, DNA, RNA, and protein was isolated. Promoter methylation and expression of p53 was measured using qPCR and Western blot. RNA immuno-precipitation was used to determine m6A-p53 levels. The expression of m6A methyltransferases (METTL3 and METTL14), demethylases (FTO and ALKBH5), and readers (YTHDF1-3 and YTHDC2) were measured using qPCR. FA induced p53 promoter hypermethylation (p < 0.0001) and decreased p53 expression (p < 0.0001). FA decreased m6A-p53 levels (p < 0.0001) by decreasing METTL3 (p < 0.0001) and METTL14 (p < 0.0001); and suppressed expression of YTHDF1 (p < 0.0001), YTHDF3 (p < 0.0001), and YTHDC2 (p < 0.0001) that ultimately reduced p53 translation (p < 0.0001). Taken together, the data shows that FA epigenetically decreased p53 expression by altering its promoter methylation and m6A RNA methylation in HepG2 cells. This study reveals a mechanism for p53 regulation by FA and provides insight into future therapeutic interventions.

SUBMITTER: Ghazi T

PROVIDER: S-EPMC7889137 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectiveEpigenetic aberration plays an important role in the development and progression of hepatocellular carcinoma (HCC). However, the alteration of RNA N6-methyladenosine (m6A) modifications and its role in HCC progression remain unclear. We therefore aimed to provide evidence using bioinformatics analysis.MethodsWe comprehensively analyzed the m6A regulator modification patterns of 605 HCC samples and correlated them with metabolic alteration characteristics. We elucidated 390 gene-based m6A-related signatures and defined an m6Ascore to quantify m6A modifications. We then assessed their values for predicting prognoses and therapeutic responses in HCC patients.ResultsWe identified 3 distinct m6A modification patterns in HCC, and each pattern had distinct metabolic characteristics. The evaluation of m6A modification patterns using m6Ascores could predict the prognoses, tumor stages, and responses to sorafenib treatments of HCC patients. A nomogram based on m6Ascores showed high accuracy in predicting the overall survival of patients. The area under the receiver operating characteristic curve of predictions of 1, 3, and 5-year overall survivals were 0.71, 0.69, and 0.70 in the training cohort, and in the test cohort it was 0.74, 0.75, and 0.71, respectively. M6Acluster C1, which corresponded to hypoactive mRNA methylation, lower expression of m6A regulators, and a lower m6Ascore, was characterized by metabolic hyperactivity, lower tumor stage, better prognosis, and lower response to sorafenib treatment. In contrast, m6Acluster C3 was distinct in its hyperactive mRNA methylations, higher expression of m6A regulators, and higher m6Ascores, and was characterized by hypoactive metabolism, advanced tumor stage, poorer prognosis, and a better response to sorafenib. The m6Acluster, C2, was intermediate between C1 and C3.ConclusionsHCCs harbored distinct m6A regulator modification patterns that contributed to the metabolic heterogeneity and diversity of HCC. Development of m6A gene signatures and the m6Ascore provides a more comprehensive understanding of m6A modifications in HCC, and helps predict the prognosis and treatment response.

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Fusaric acid decreases p53 expression by altering promoter methylation and m6A RNA methylation in human hepatocellular carcinoma (HepG2) cells.

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