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Hypoxia, Epithelial-Mesenchymal Transition, and TET-Mediated Epigenetic Changes

Research Center for Tumor Medical Science and Graduate Institute of Cancer Biology, China Medical University, Taichung 40402, Taiwan
Institute of Clinical Medicine, China Medical University, Taichung 40402, Taiwan
Authors to whom correspondence should be addressed.
Academic Editors: David A. Brenner, Tatiana Kisseleva and Jonas Fuxe
J. Clin. Med. 2016, 5(2), 24;
Received: 29 November 2015 / Revised: 15 January 2016 / Accepted: 26 January 2016 / Published: 4 February 2016
(This article belongs to the Special Issue Epithelial-Mesenchymal Transition)
PDF [797 KB, uploaded 4 February 2016]


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. View Full-Text
Keywords: TET; 5hmC; DNA demethylation; hypoxia; HAP TET; 5hmC; DNA demethylation; hypoxia; HAP

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Kao, S.-H.; Wu, K.-J.; Lee, W.-H. Hypoxia, Epithelial-Mesenchymal Transition, and TET-Mediated Epigenetic Changes. J. Clin. Med. 2016, 5, 24.

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