PDF(Pubmed)
Abstract：
Ten-eleven translocation 1 (TET1) is a methylcytosine dioxygenase involved in active DNA demethylation. In our previous study, we demonstrated that TET1 reprogrammed the ovarian cancer epigenome, increased stem properties, and activated various regulatory networks, including metabolic networks. However, the role of TET1 in cancer metabolism remains poorly understood. Herein, we uncovered a demethylated metabolic gene network, especially oxidative phosphorylation (OXPHOS). Contrary to the concept of the Warburg effect in cancer cells, TET1 increased energy production mainly using OXPHOS rather than using glycolysis. Notably, TET1 increased the mitochondrial mass and DNA copy number. TET1 also activated mitochondrial biogenesis genes and adenosine triphosphate production. However, the reactive oxygen species levels were surprisingly decreased. In addition, TET1 increased the basal and maximal respiratory capacities. In an analysis of tricarboxylic acid cycle metabolites, TET1 increased the levels of α-ketoglutarate, which is a coenzyme of TET1 dioxygenase and may provide a positive feedback loop to modify the epigenomic landscape. TET1 also increased the mitochondrial complex I activity. Moreover, the mitochondrial complex I inhibitor, which had synergistic effects with the casein kinase 2 inhibitor, affected ovarian cancer growth. Altogether, TET1-reprogrammed ovarian cancer stem cells shifted the energy source to OXPHOS, which suggested that metabolic intervention might be a novel strategy for ovarian cancer treatment.
摘要：
十-十一易位1（TET1）是参与活性DNA去甲基化的甲基胞嘧啶双加氧酶。在我们之前的研究中,我们证明了TET1重新编程了卵巢癌表观基因组，增加了茎的性质，并激活了各种监管网络，包括代谢网络。然而,TET1在癌症代谢中的作用仍然知之甚少.在这里，我们发现了一个去甲基化的代谢基因网络，尤其是氧化磷酸化（OXPHOS）。与癌细胞中Warburg效应的概念相反，TET1主要使用OXPHOS而不是使用糖酵解来增加能量产生。值得注意的是,TET1增加了线粒体质量和DNA拷贝数。TET1还激活线粒体生物发生基因和三磷酸腺苷的产生。然而,活性氧水平令人惊讶地下降。此外,TET1增加了基础和最大呼吸能力。在对三羧酸循环代谢物的分析中，TET1增加了α-酮戊二酸的水平，它是TET1双加氧酶的辅酶，可能提供正反馈回路来修饰表观基因组景观。TET1还增加了线粒体复合物I的活性。此外，线粒体复合物I抑制剂，与酪蛋白激酶2抑制剂有协同作用，影响卵巢癌生长。总之,TET1重编程的卵巢癌干细胞将能量来源转移到OXPHOS，这表明代谢干预可能是卵巢癌治疗的新策略。
