title: Hypoxia, Epithelial-Mesenchymal Transition, and TET-Mediated Epigenetic Changes.
abstract: 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.
authors: Research Center for Tumor Medical Science and Graduate Institute of Cancer Biology, China Medical University, Taichung 40402, Taiwan. shkao@mail.cmu.edu.tw.
authors: Shih-Han
authors: SH
authors: Kao
authors: Research Center for Tumor Medical Science and Graduate Institute of Cancer Biology, China Medical University, Taichung 40402, Taiwan. wukj@mail.cmu.edu.tw.
authors: Kou-Juey
authors: KJ
authors: Wu
authors: Institute of Clinical Medicine, China Medical University, Taichung 40402, Taiwan. whlee@uci.edu.
authors: Wen-Hwa
authors: WH
authors: Lee
keywords: 5hmC; DNA demethylation; HAP; TET; hypoxia