The Korean journal of internal medicine

The Korean Association of Internal Medicine (대한내과학회)
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The role of hypoxia on the acquisition of epithelial-mesenchymal transition and cancer stemness: a possible link to epigenetic regulation

  • Yeo, Chang Dong (Division of Pulmonology, Department of Internal Medicine, The Cancer Research Institute, College of Medicine, The Catholic University of Korea) ;
  • Kang, Nahyeon (Division of Pulmonology, Department of Internal Medicine, The Cancer Research Institute, College of Medicine, The Catholic University of Korea) ;
  • Choi, Su Yeon (Division of Pulmonology, Department of Internal Medicine, The Cancer Research Institute, College of Medicine, The Catholic University of Korea) ;
  • Kim, Bit Na (Division of Pulmonology, Department of Internal Medicine, The Cancer Research Institute, College of Medicine, The Catholic University of Korea) ;
  • Park, Chan Kwon (Division of Pulmonology, Department of Internal Medicine, The Cancer Research Institute, College of Medicine, The Catholic University of Korea) ;
  • Kim, Jin Woo (Division of Pulmonology, Department of Internal Medicine, The Cancer Research Institute, College of Medicine, The Catholic University of Korea) ;
  • Kim, Young Kyoon (Division of Pulmonology, Department of Internal Medicine, The Cancer Research Institute, College of Medicine, The Catholic University of Korea) ;
  • Kim, Seung Joon (Division of Pulmonology, Department of Internal Medicine, The Cancer Research Institute, College of Medicine, The Catholic University of Korea)
  • Received : 2016.09.29
  • Accepted : 2017.06.15
  • Published : 2017.07.01
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Abstract

A hypoxic microenvironment leads to cancer progression and increases the metastatic potential of cancer cells within tumors via epithelial-mesenchymal transition (EMT) and cancer stemness acquisition. The hypoxic response pathway can occur under oxygen tensions of < 40 mmHg through hypoxia-inducible factors (HIFs), which are considered key mediators in the adaptation to hypoxia. Previous studies have shown that cellular responses to hypoxia are required for EMT and cancer stemness maintenance through $HIF-1{\alpha}$ and $HIF-2{\alpha}$. The principal transcription factors of EMT include Twist, Snail, Slug, Sip1 (Smad interacting protein 1), and ZEB1 (zinc finger E-box-binding homeobox 1). HIFs bind to hypoxia response elements within the promoter region of these genes and also target cancer stem cell-associated genes and mediate transcriptional responses to hypoxia during stem cell differentiation. Acquisition of stemness characteristics in epithelial cells can be induced by activation of the EMT process. The mechanism of these phenotypic changes includes epigenetic alterations, such as DNA methylation, histone modification, chromatin remodeling, and microRNAs. Increased expression of EMT and pluripotent genes also play a role through demethylation of their promoters. In this review, we summarize the role of hypoxia on the acquisition of EMT and cancer stemness and the possible association with epigenetic regulation, as well as their therapeutic applications.

Keywords

Acknowledgement

Supported by : National Research Foundation of Korea (NRF)

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