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

Epigenetics. 2022 Aug;17(8):894-905. doi: 10.1080/15592294.2021.1971372. Epub 2021 Sep 8.

Abstract

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.

Keywords: DNA methylation; HIF1A; VHL; hypoxia; kidney cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alcohol Oxidoreductases / genetics
  • Alcohol Oxidoreductases / metabolism
  • Carcinoma, Renal Cell* / genetics
  • DNA / metabolism
  • DNA Methylation
  • Humans
  • Hypoxia / genetics
  • Isocitrate Dehydrogenase
  • Kidney Neoplasms* / metabolism
  • Von Hippel-Lindau Tumor Suppressor Protein / genetics
  • Von Hippel-Lindau Tumor Suppressor Protein / metabolism

Substances

  • DNA
  • Alcohol Oxidoreductases
  • Isocitrate Dehydrogenase
  • L2HGDH protein, human
  • Von Hippel-Lindau Tumor Suppressor Protein
  • VHL protein, human

Grants and funding

This work was partially supported by Russian Science Foundation grant #19-14-00347 for all authors except JS, MM, MG and DG who are members of University Center of Excellence ‘Towards Personalized Medicine’ operating under Excellence Initiative – Research University in Nicolaus Copernicus University in Toruń. Part of this work has been carried out using computing resources of the federal collective usage center Complex for Simulation and Data Processing for Mega-science Facilities at NRC ‘Kurchatov Institute,’ http://ckp.nrcki.ru/.