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

  1. Hui Yang1,2,
  2. Wei Xu2,
  3. Shenghong Ma1,2,
  4. Huaipeng Lin1,2,
  5. Honguang Zhu3,4,
  6. Lixia Liu5,
  7. Ying Liu3,4,
  8. Chen Yang5,
  9. Yanhui Xu1,
  10. Shimin Zhao2,
  11. Dan Ye1,8,
  12. Yue Xiong1,2,6,8 and
  13. Kun-Liang Guan1,4,7
  14. 1Molecular and Cell Biology Laboratory, Institutes of Biomedical Sciences,
  15. 2College of Life Science,
  16. 3Department of Pathology,
  17. 4Shanghai Medical College, Fudan University, Shanghai 200032, China;
  18. 5Institute of Plant Physiology and Ecology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200032, China;
  19. 6Lineberger Comprehensive Cancer Center, Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA;
  20. 7Department of Pharmacology and Moores Cancer Center, University of California at San Diego, La Jolla, California 92093, USA

Abstract

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.

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