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.

Hyperglycemia Increases Interstitial Cells of Cajal via MAPK1 and MAPK3 Signaling to ETV1 and KIT, Leading to Rapid Gastric Emptying

“…B6.Cg- Gt(ROSA)26Sor tm1(rtTA*M2)Jae /J;B6.Cg-Tg(tetO-cre)1Jaw/J ;Sdhc fl/fl ( R26 M2rtTA/+ ;Tg tetO-cre ; Sdhc fl/fl ) mice and R26 M2rtTA/+ ; Sdhc fl/fl controls (4 males and 4 females per genotype) carrying loxP sites flanking exon 4 of Sdhc encoding subunit C of the tricarboxylic acid (TCA) cycle enzyme and electron transfer chain complex succinate dehydrogenase, were generated as described in ref. 26 and the Supplementary Methods. Deletion of Sdhc exon 4 was induced after weaning by inclusion of 2 mg/mL doxycycline hyclate (Sigma-Aldrich, St. Louis, MO) and 5 mg/mL sucrose in the drinking water for 20 days.…”

“…B6.Cg-Tg(CAG-cre/Esr1*)5Amc/J; Sdhc fl/− (Tg CAG-creERTM/+ ; Sdhc fl/− ) and Sdhc fl/− mice (2 males and 2 females per genotype) used as an additional model have been described previously. 26 For Sdhc inactivation, tamoxifen diet (Harlan Laboratories, Madison, WI) was started at 2–5 mo of age and maintained for 14–18 mo until time of sacrifice (see also Supplementary Methods). Homozygous H-2K b -tsA58 transgenic mice (Immortomice ® ; CBA;B10-Tg(H2K b -tsA58)6Kio/Crl) harboring the temperature-sensitive simian virus 40 tsA58 mutant large T antigen (tsTAg) 27 were from Charles River Laboratories (Wilmington, MA).…”

Pheochromocytoma: Gasping for Air

“…All these metabolic changes result in a metabolic shift from OXPHOS to aerobic glycolysis with further Bgasping for air^by TCA metabolite-specific activation of the HIF signaling pathway. HIF-α stabilization and inhibition of α-KG-dependent dioxygenases was described in VHL-and SDHx-mutated tumors [28, [134][135][136][137][138][139]. HIF enhances the glycolytic pathway by increasing expression of target genes involved in the glycolytic and anabolic processes (glucose transporters (GLUT) 1, 2, hexokinase (HK) 2, PKM2, LDH-A) [34,140].…”

Regulation and Functional Significance of 5-Hydroxymethylcytosine in Cancer

“…Intriguingly, gliomas with IDH1/2 mutation show reduced angiogenesis and low expression of HIG mRNA, adding evidence to prove the significant role of 5hmC in hypoxia [88]. In paraganglioma, a common cancer prevalent in hypoxic environments like high altitudes, SDH mutation is linked to poor survival suggesting possible involvement of 5hmC imbalance [89]. Increased cellular concentrations of oncometabolites like fumarate can also stabilize HIF1A, invoking changes in the pattern of gene expression which distinctly shows an additional layer of regulation by 5hmC and TET under hypoxic conditions [90].…”