Oxygen Concentration controls epigenetic effects in models of familial paraganglioma

Yeng F. Her, Molly Nelson-Holte, Louis James Maher

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

Familial paraganglioma (PGL) is a rare neuroendocrine cancer associated with defects in the genes encoding the subunits of succinate dehydrogenase (SDH), a tricarboxylic acid (TCA) cycle enzyme. For unknown reasons, a higher prevalence of PGL has been reported for humans living at higher altitude, with increased disease aggressiveness and morbidity. In this study, we evaluate the effects of oxygen on epigenetic changes due to succinate accumulation in three SDH loss cell culture models. We test the hypothesis that the mechanism of α-ketoglutarate (α-KG)-dependent dioxygenase enzymes explains the inhibitory synergy of hypoxia and succinate accumulation. We confirm that SDH loss leads to profound succinate accumulation. We further show that hypoxia and succinate accumulation synergistically inhibit α-KG-dependent dioxygenases leading to increased stabilization of transcription factor HIF1α, HIF2α, and hypermethylation of histones and DNA. Increasing oxygen suppresses succinate inhibition of α-KG-dependent dioxygenases. This result provides a possible explanation for the association between hypoxia and PGL, and suggests hyperoxia as a potential novel therapy.

Original languageEnglish (US)
Article numbere0127471
JournalPloS one
Volume10
Issue number5
DOIs
StatePublished - May 18 2015

ASJC Scopus subject areas

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

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