Inhibition of α-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors

Genes Dev. 2012 Jun 15;26(12):1326-38. doi: 10.1101/gad.191056.112. Epub 2012 Jun 7.


Two Krebs cycle genes, fumarate hydratase (FH) and succinate dehydrogenase (SDH), are mutated in a subset of human cancers, leading to accumulation of their substrates, fumarate and succinate, respectively. Here we demonstrate that fumarate and succinate are competitive inhibitors of multiple α-ketoglutarate (α-KG)-dependent dioxygenases, including histone demethylases, prolyl hydroxylases, collagen prolyl-4-hydroxylases, and the TET (ten-eleven translocation) family of 5-methlycytosine (5mC) hydroxylases. Knockdown of FH and SDH results in elevated intracellular levels of fumarate and succinate, respectively, which act as competitors of α-KG to broadly inhibit the activity of α-KG-dependent dioxygenases. In addition, ectopic expression of tumor-derived FH and SDH mutants inhibits histone demethylation and hydroxylation of 5mC. Our study suggests that tumor-derived FH and SDH mutations accumulate fumarate and succinate, leading to enzymatic inhibition of multiple α-KG-dependent dioxygenases and consequent alterations of genome-wide histone and DNA methylation. These epigenetic alterations associated with mutations of FH and SDH likely contribute to tumorigenesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biocatalysis / drug effects
  • Cells, Cultured
  • DNA Methylation / drug effects
  • Dioxygenases / metabolism
  • Endostatins / metabolism
  • Fumarate Hydratase / genetics*
  • Fumarates / chemistry
  • Fumarates / pharmacology*
  • Gene Expression Regulation / drug effects
  • Gene Knockdown Techniques
  • Genome, Human / genetics
  • HEK293 Cells
  • Histone Demethylases / metabolism*
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Ketoglutaric Acids / chemistry
  • Ketoglutaric Acids / pharmacology*
  • Mice
  • Models, Biological
  • Mutation / genetics*
  • Succinate Dehydrogenase / genetics*
  • Succinic Acid / chemistry
  • Succinic Acid / pharmacology*
  • Tumor Suppressor Proteins / genetics


  • Endostatins
  • Fumarates
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Ketoglutaric Acids
  • Tumor Suppressor Proteins
  • Succinic Acid
  • Dioxygenases
  • Histone Demethylases
  • Succinate Dehydrogenase
  • Fumarate Hydratase