An IDH-independent mechanism of DNA hypermethylation upon VHL inactivation in cancer

Artemov, A. V.; Zhenilo, S.; Kaplun, D.; Starshin, A.; Sokolov, A.; Mazur, A. M.; Szpotan, J.; Gawronski, M.; Modrzejewska, M.; Gackowski, D.; Prokhortchouk, E. B.

doi:10.1101/2020.12.09.418616

bioRxiv · 10.1101/2020.12.09.418616

An IDH-independent mechanism of DNA hypermethylation upon VHL inactivation in cancer

Artemov, A. V.·Zhenilo, S.·Kaplun, D.·Starshin, A.·Sokolov, A.·Mazur, A. M.·Szpotan, J.·Gawronski, M.·Modrzejewska, M.·Gackowski, D.·Prokhortchouk, E. B.

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Abstract

Hypermethylation of tumor suppressors and other aberrations of DNA methylation in tumors 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 transcription program associated with HIF1a transcription factor. VHL inactivation by genetic or epigenetic events, which also induces aberrant activation of HIF1a, is the most common driver event for renal cancer. With whole-genome bisulfite 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 show 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 IDH wild type cells. Key pointsO_LIInactivation of VHL gene leads to genome hypermethylation in kidney cancer cells. The DNA methylation phenotype can be rescued by endogenous expression of wild-type VHL. C_LIO_LIDNA hypermethylation can be attributed to the accumulation of a Tet inhibitor 2-hydroxyglutarate C_LIO_LIThe accumulation of 2-hydroxyglutarate in IDH wild-type cells is explained by gene expression changes in key metabolic enzymes (malate dehydrogenase MDH and 2-hydroxyglutrarate dehydrogenase L2HGDH). C_LI

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Artemov, A. V., Zhenilo, S., Kaplun, D., Starshin, A., Sokolov, A., Mazur, A. M., Szpotan, J., Gawronski, M., Modrzejewska, M., Gackowski, D., Prokhortchouk, E. B.. 2020-12-10. An IDH-independent mechanism of DNA hypermethylation upon VHL inactivation in cancer. https://doi.org/10.1101/2020.12.09.418616

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