Hypoxia, Epithelial-Mesenchymal Transition, and TET-Mediated Epigenetic Changes.
Hypoxia, Epithelial-Mesenchymal Transition, and TET-Mediated Epigenetic Changes.
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缺氧，上皮间质转变和TET介导的表观遗传变化。
DOI：
10.3390/jcm5020024
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发表时间：
2016-02-04
影响因子：
3.9
通讯作者：
Lee WH
中科院分区：
文献类型：
--
作者：
Kao SH;Wu KJ;Lee WH
肿瘤缺氧是微循环破坏和氧气供应不足的病理生理结果，导致增殖增强、上皮-间质转化（EMT）、转移和化学抗性。由缺氧诱导的表观遗传变化被充分记录，并且它们导致肿瘤进展。最近的研究表明，由10 - 11易位（泰特）蛋白介导的DNA去甲基化诱导主要的表观遗传学变化，并控制癌症发展的关键步骤。泰特酶作为5 mC（5-甲基胞嘧啶）特异性双加氧酶并引起DNA去甲基化。缺氧激活TET 1的表达，TET 1作为HIF-1α转录调控的共激活因子，调节HIF-1α下游靶基因，促进上皮-间质转化。由于HIF是肿瘤进展的负性预后因子，低氧激活的前药（HAP）可能提供有利的治疗方法来减轻低氧诱导的恶性肿瘤。
Tumor hypoxia is a pathophysiologic outcome of disrupted microcirculation with inadequate supply of oxygen, leading to enhanced proliferation, epithelial-mesenchymal transition (EMT), metastasis, and chemo-resistance. Epigenetic changes induced by hypoxia are well documented, and they lead to tumor progression. Recent advances show that DNA demethylation mediated by the Ten-eleven translocation (TET) proteins induces major epigenetic changes and controls key steps of cancer development. TET enzymes serve as 5mC (5-methylcytosine)-specific dioxygenases and cause DNA demethylation. Hypoxia activates the expression of TET1, which also serves as a co-activator of HIF-1α transcriptional regulation to modulate HIF-1α downstream target genes and promote epithelial-mesenchymal transition. As HIF is a negative prognostic factor for tumor progression, hypoxia-activated prodrugs (HAPs) may provide a favorable therapeutic approach to lessen hypoxia-induced malignancy.