2-hydroxyglutarate drives whole-genome hypermethylation in kidney cancer cells with inactivated VHL

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 the accumulation of 2-hydroxyglutarate -- a metabolite that inhibits DNA demethylation by Tet enzymes. Overall design: We profiled genome-wide DNA methylation with whole-genome bisulfite sequencing (wgBS) in three clones with independent VHL inactivation and observed global genome hypermethylation. Reexpression of exogenous wild-type VHL has partially rescued DNA methylation phenotype to wild-type state.Hypermethylawe profiled genome-wide DNA methylation with bisulfite sequencing (wgBS) in three clones with independent VHL inactivation and observed global genome hypermethylation. Reexpression of exogenous wild-type VHL has partially rescued DNA methylation phenotype to wild-type state. tion 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 the accumulation of 2-hydroxyglutarate -- a metabolite that inhibits DNA demethylation by Tet enzymes.