Fumonisin B<sub>1</sub> Epigenetically Regulates PTEN Expression and Modulates DNA Damage Checkpoint Regulation in HepG2 Liver Cells
Fumonisin B<sub>1</sub> (FB<sub>1</sub>), a <i>Fusarium</i>-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 FB&...
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MDPI AG
2020-09-01
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| Series: | Toxins |
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| Online Access: | https://www.mdpi.com/2072-6651/12/10/625 |
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| author | Thilona Arumugam Terisha Ghazi Anil Chuturgoon |
| author_facet | Thilona Arumugam Terisha Ghazi Anil Chuturgoon |
| author_sort | Thilona Arumugam |
| collection | DOAJ |
| description | Fumonisin B<sub>1</sub> (FB<sub>1</sub>), a <i>Fusarium</i>-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 FB<sub>1</sub>-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 FB<sub>1</sub> (IC<sub>50</sub>: 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. FB<sub>1</sub> 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, FB<sub>1</sub> epigenetically modulates the PTEN/PI3K/AKT signaling cascade, preventing DNA damage checkpoint regulation, and induces significant DNA damage. |
| first_indexed | 2024-03-10T15:55:45Z |
| format | Article |
| id | doaj.art-40fd5fa3be1c4df6a9c24173bc4527c9 |
| institution | Directory Open Access Journal |
| issn | 2072-6651 |
| language | English |
| last_indexed | 2024-03-10T15:55:45Z |
| publishDate | 2020-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Toxins |
| spelling | doaj.art-40fd5fa3be1c4df6a9c24173bc4527c92023-11-20T15:38:25ZengMDPI AGToxins2072-66512020-09-01121062510.3390/toxins12100625Fumonisin B<sub>1</sub> Epigenetically Regulates PTEN Expression and Modulates DNA Damage Checkpoint Regulation in HepG2 Liver CellsThilona Arumugam0Terisha Ghazi1Anil Chuturgoon2Discipline of Medical Biochemistry and Chemical Pathology, School of Laboratory Medicine and Medical Sciences, College of Health Sciences, George Campbell Building, Howard College, University of KwaZulu-Natal, Durban 4041, South AfricaDiscipline of Medical Biochemistry and Chemical Pathology, School of Laboratory Medicine and Medical Sciences, College of Health Sciences, George Campbell Building, Howard College, University of KwaZulu-Natal, Durban 4041, South AfricaDiscipline of Medical Biochemistry and Chemical Pathology, School of Laboratory Medicine and Medical Sciences, College of Health Sciences, George Campbell Building, Howard College, University of KwaZulu-Natal, Durban 4041, South AfricaFumonisin B<sub>1</sub> (FB<sub>1</sub>), a <i>Fusarium</i>-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 FB<sub>1</sub>-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 FB<sub>1</sub> (IC<sub>50</sub>: 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. FB<sub>1</sub> 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, FB<sub>1</sub> epigenetically modulates the PTEN/PI3K/AKT signaling cascade, preventing DNA damage checkpoint regulation, and induces significant DNA damage.https://www.mdpi.com/2072-6651/12/10/625Fumonisin B<sub>1</sub>DNA damageepigeneticsPTENH3K4me3Checkpoint Kinase 1 |
| spellingShingle | Thilona Arumugam Terisha Ghazi Anil Chuturgoon Fumonisin B<sub>1</sub> Epigenetically Regulates PTEN Expression and Modulates DNA Damage Checkpoint Regulation in HepG2 Liver Cells Toxins Fumonisin B<sub>1</sub> DNA damage epigenetics PTEN H3K4me3 Checkpoint Kinase 1 |
| title | Fumonisin B<sub>1</sub> Epigenetically Regulates PTEN Expression and Modulates DNA Damage Checkpoint Regulation in HepG2 Liver Cells |
| title_full | Fumonisin B<sub>1</sub> Epigenetically Regulates PTEN Expression and Modulates DNA Damage Checkpoint Regulation in HepG2 Liver Cells |
| title_fullStr | Fumonisin B<sub>1</sub> Epigenetically Regulates PTEN Expression and Modulates DNA Damage Checkpoint Regulation in HepG2 Liver Cells |
| title_full_unstemmed | Fumonisin B<sub>1</sub> Epigenetically Regulates PTEN Expression and Modulates DNA Damage Checkpoint Regulation in HepG2 Liver Cells |
| title_short | Fumonisin B<sub>1</sub> Epigenetically Regulates PTEN Expression and Modulates DNA Damage Checkpoint Regulation in HepG2 Liver Cells |
| title_sort | fumonisin b sub 1 sub epigenetically regulates pten expression and modulates dna damage checkpoint regulation in hepg2 liver cells |
| topic | Fumonisin B<sub>1</sub> DNA damage epigenetics PTEN H3K4me3 Checkpoint Kinase 1 |
| url | https://www.mdpi.com/2072-6651/12/10/625 |
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