title: Oxygen concentration controls epigenetic effects in models of familial paraganglioma.
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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, 200 First St. SW, Rochester, MN, 55905, United States of America; Mayo Graduate School, Mayo Medical School and the Mayo Clinic Medical Scientist Training Program, 200 First St. SW, Rochester, MN, 55905, United States of America.
authors.forename: Yeng F
authors.initials: YF
authors.lastname: Her
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, 200 First St. SW, Rochester, MN, 55905, United States of America.
authors.forename: Molly
authors.initials: M
authors.lastname: Nelson-Holte
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, 200 First St. SW, Rochester, MN, 55905, United States of America.
authors.forename: Louis James
authors.initials: LJ
authors.lastname: Maher
mesh_terms: D044503:5-Methylcytosine / Q000031:analogs & derivatives; D000818:Animals; D016022:Case-Control Studies; D003596:Cytosine / Q000031:analogs & derivatives / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects; D049308:Dioxygenases / Q000037:antagonists & inhibitors / Q000378:metabolism; D044127:Epigenesis, Genetic / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007656:Ketoglutaric Acids / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D010100:Oxygen / Q000378:metabolism*; D010235:Paraganglioma / Q000235:genetics*; D013385:Succinate Dehydrogenase / Q000378:metabolism; D019802:Succinic Acid / Q000494:pharmacology
chemical_list: D006657:Histones; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007656:Ketoglutaric Acids; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D003596:Cytosine; D019802:Succinic Acid; D049308:Dioxygenases; D013385:Succinate Dehydrogenase; D010100:Oxygen