An IDH-independent mechanism of DNA hypermethylation upon VHL inactivation in cancer
Hypermethylation of tumour suppressors and other aberrations of DNA methylation in tumours play a significant role in cancer progression. DNA methylation can be affected by various environmental conditions, including hypoxia. The response to hypoxia is mainly achieved through activation of the trans...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2022-08-01
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| Series: | Epigenetics |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/15592294.2021.1971372 |
| _version_ | 1797678796148572160 |
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| author | Artem V. Artemov Svetlana Zhenilo Daria Kaplun Alexey Starshin Alexey Sokolov Alexander M. Mazur Justyna Szpotan Maciej Gawronski Martyna Modrzejewska Daniel Gackowski Egor B. Prokhortchouk |
| author_facet | Artem V. Artemov Svetlana Zhenilo Daria Kaplun Alexey Starshin Alexey Sokolov Alexander M. Mazur Justyna Szpotan Maciej Gawronski Martyna Modrzejewska Daniel Gackowski Egor B. Prokhortchouk |
| author_sort | Artem V. Artemov |
| collection | DOAJ |
| description | Hypermethylation of tumour suppressors and other aberrations of DNA methylation in tumours play a significant role in cancer progression. DNA methylation can be affected by various environmental conditions, including hypoxia. The response to hypoxia is mainly achieved through activation of the transcriptional program associated with HIF1A transcription factor. Inactivation of Von Hippel-Lindau Tumour Suppressor gene (VHL) by genetic or epigenetic events, which also induces aberrant activation of HIF1A, is the most common driver event for renal cancer. With whole-genome bisulphite sequencing and LC-MS, we demonstrated that VHL inactivation induced global genome hypermethylation in human kidney cancer cells under normoxic conditions. This effect was reverted by exogenous expression of wild-type VHL. We showed that global genome hypermethylation in VHL mutants can be explained by transcriptional changes in MDH and L2HGDH genes that cause the accumulation of 2-hydroxyglutarate – a metabolite that inhibits DNA demethylation by TET enzymes. Unlike the known cases of DNA hypermethylation in cancer, 2-hydroxyglutarate was accumulated in the cells with the wild-type isocitrate dehydrogenases. |
| first_indexed | 2024-03-11T23:05:08Z |
| format | Article |
| id | doaj.art-08abffbbc197416ba2aac5ec28148eb7 |
| institution | Directory Open Access Journal |
| issn | 1559-2294 1559-2308 |
| language | English |
| last_indexed | 2024-03-11T23:05:08Z |
| publishDate | 2022-08-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Epigenetics |
| spelling | doaj.art-08abffbbc197416ba2aac5ec28148eb72023-09-21T13:09:26ZengTaylor & Francis GroupEpigenetics1559-22941559-23082022-08-0117889490510.1080/15592294.2021.19713721971372An IDH-independent mechanism of DNA hypermethylation upon VHL inactivation in cancerArtem V. Artemov0Svetlana Zhenilo1Daria Kaplun2Alexey Starshin3Alexey Sokolov4Alexander M. Mazur5Justyna Szpotan6Maciej Gawronski7Martyna Modrzejewska8Daniel Gackowski9Egor B. Prokhortchouk10Research Center of Biotechnology RASResearch Center of Biotechnology RASResearch Center of Biotechnology RASResearch Center of Biotechnology RASResearch Center of Biotechnology RASResearch Center of Biotechnology RASNicolaus Copernicus University in ToruńNicolaus Copernicus University in ToruńNicolaus Copernicus University in ToruńNicolaus Copernicus University in ToruńResearch Center of Biotechnology RASHypermethylation of tumour suppressors and other aberrations of DNA methylation in tumours play a significant role in cancer progression. DNA methylation can be affected by various environmental conditions, including hypoxia. The response to hypoxia is mainly achieved through activation of the transcriptional program associated with HIF1A transcription factor. Inactivation of Von Hippel-Lindau Tumour Suppressor gene (VHL) by genetic or epigenetic events, which also induces aberrant activation of HIF1A, is the most common driver event for renal cancer. With whole-genome bisulphite sequencing and LC-MS, we demonstrated that VHL inactivation induced global genome hypermethylation in human kidney cancer cells under normoxic conditions. This effect was reverted by exogenous expression of wild-type VHL. We showed that global genome hypermethylation in VHL mutants can be explained by transcriptional changes in MDH and L2HGDH genes that cause the accumulation of 2-hydroxyglutarate – a metabolite that inhibits DNA demethylation by TET enzymes. Unlike the known cases of DNA hypermethylation in cancer, 2-hydroxyglutarate was accumulated in the cells with the wild-type isocitrate dehydrogenases.http://dx.doi.org/10.1080/15592294.2021.1971372dna methylationvhlhypoxiahif1akidney cancer |
| spellingShingle | Artem V. Artemov Svetlana Zhenilo Daria Kaplun Alexey Starshin Alexey Sokolov Alexander M. Mazur Justyna Szpotan Maciej Gawronski Martyna Modrzejewska Daniel Gackowski Egor B. Prokhortchouk An IDH-independent mechanism of DNA hypermethylation upon VHL inactivation in cancer Epigenetics dna methylation vhl hypoxia hif1a kidney cancer |
| title | An IDH-independent mechanism of DNA hypermethylation upon VHL inactivation in cancer |
| title_full | An IDH-independent mechanism of DNA hypermethylation upon VHL inactivation in cancer |
| title_fullStr | An IDH-independent mechanism of DNA hypermethylation upon VHL inactivation in cancer |
| title_full_unstemmed | An IDH-independent mechanism of DNA hypermethylation upon VHL inactivation in cancer |
| title_short | An IDH-independent mechanism of DNA hypermethylation upon VHL inactivation in cancer |
| title_sort | idh independent mechanism of dna hypermethylation upon vhl inactivation in cancer |
| topic | dna methylation vhl hypoxia hif1a kidney cancer |
| url | http://dx.doi.org/10.1080/15592294.2021.1971372 |
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