Her Yeng F, Nelson-Holte Molly, Maher Louis James
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.
Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, 200 First St. SW, Rochester, MN, 55905, United States of America.
PLoS One. 2015 May 18;10(5):e0127471. doi: 10.1371/journal.pone.0127471. eCollection 2015.
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.
家族性副神经节瘤（PGL）是一种罕见的神经内分泌癌，与编码三羧酸（TCA）循环酶琥珀酸脱氢酶（SDH）亚基的基因突变有关。出于未知原因，据报道生活在高海拔地区的人群中PGL的患病率较高，且疾病侵袭性和发病率增加。在本研究中，我们评估了氧气对三种SDH缺失细胞培养模型中因琥珀酸积累而导致的表观遗传变化的影响。我们检验了以下假设：α-酮戊二酸（α-KG）依赖性双加氧酶的机制解释了缺氧与琥珀酸积累的抑制协同作用。我们证实SDH缺失会导致大量琥珀酸积累。我们进一步表明，缺氧和琥珀酸积累协同抑制α-KG依赖性双加氧酶，导致转录因子HIF1α、HIF2α稳定性增加以及组蛋白和DNA的高甲基化。增加氧气可抑制琥珀酸对α-KG依赖性双加氧酶的抑制作用。这一结果为缺氧与PGL之间的关联提供了一种可能的解释，并提示高氧作为一种潜在的新疗法。
