Intermediary metabolite precursor dimethyl-2-ketoglutarate stabilizes hypoxia-inducible factor-1α by inhibiting prolyl-4-hydroxylase PHD2

Peifeng Hou, Ching Ying Kuo, Chun Ting Cheng, Jing Ping Liou, David K. Ann, Qiang Chen

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Hypoxia-inducible factor 1 a (HIF-1α), a major mediator of tumor physiology, is activated during tumor progression, and its abundance is correlated with therapeutic resistance in a broad range of solid tumors. The accumulation of HIF-1α is mainly caused by hypoxia or through the mutated succinate dehydrogenase A (SDHA) or fumarate hydratase (FH) expression to inhibit its degradation. However, its activation under normoxic conditions, termed pseudohypoxia, in cells without mutated SDHA or FH is not well documented. Here, we show that dimethyl-2-ketoglutarate (DKG), a cell membrane-permeable precursor of a key metabolic intermediate, α-ketoglutarate (α-KG), known for its ability to rescue glutamine deficiency, transiently stabilized HIF-1α by inhibiting activity of the HIF prolyl hydroxylase domain-containing protein, PHD2. Consequently, prolonged DKGtreatment under normoxia elevated HIF-1α abundance and up-regulated the expression of its downstream target genes, thereby inducing a pseudohypoxic condition. This HIF-1α stabilization phenotype is similar to that from treatment of cells with desferrioxamine (DFO), an iron chelator, or dimethyloxalyglycine (DMOG), an established PHD inhibitor, but was not recapitulated with other α-KG analogues, such as Octyl-2KG, MPTOM001 and MPTOM002. Our study is the first example of an α-KG precursor to increase HIF-1a abundance and activity. We propose that DKG acts as a potent HIF-1α activator, highlighting the potential use of DKG to investigate the contribution of PHD2-HIF-1α pathway to tumor biology.

Original languageEnglish
Article numbere113865
JournalPLoS One
Volume9
Issue number11
DOIs
Publication statusPublished - Nov 24 2014

Fingerprint

procollagen-proline dioxygenase
Prolyl Hydroxylases
Hypoxia-Inducible Factor 1
Metabolites
metabolites
succinate dehydrogenase (quinone)
Tumors
Fumarate Hydratase
neoplasms
normoxia
Succinate Dehydrogenase
Neoplasms
deferoxamine
Deferoxamine
Physiology
Cell membranes
Chelating Agents
chelating agents
alpha-ketoglutaric acid
hypoxia-inducible factor 1

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Intermediary metabolite precursor dimethyl-2-ketoglutarate stabilizes hypoxia-inducible factor-1α by inhibiting prolyl-4-hydroxylase PHD2. / Hou, Peifeng; Kuo, Ching Ying; Cheng, Chun Ting; Liou, Jing Ping; Ann, David K.; Chen, Qiang.

In: PLoS One, Vol. 9, No. 11, e113865, 24.11.2014.

Research output: Contribution to journalArticle

Hou, Peifeng ; Kuo, Ching Ying ; Cheng, Chun Ting ; Liou, Jing Ping ; Ann, David K. ; Chen, Qiang. / Intermediary metabolite precursor dimethyl-2-ketoglutarate stabilizes hypoxia-inducible factor-1α by inhibiting prolyl-4-hydroxylase PHD2. In: PLoS One. 2014 ; Vol. 9, No. 11.
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