Epigenetics, TET proteins, and hypoxia in epithelial-mesenchymal transition and tumorigenesis.

Hypoxia in tumors is primarily a pathophysiologic consequence of structurally and functionally disturbed microcirculation with inadequate supply of oxygen. Tumor hypoxia is strongly associated with tumor propagation, malignant progression, and resistance to therapy. Aberrant epigenetic regulation plays a crucial role in the process of hypoxia-driven malignant progression. Convert of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) by ten-eleven translocation (TET) family enzymes plays important biological functions in embryonic stem cells, development, aging and disease. Recent reports showed that level of 5hmC and TET proteins was altered in various types of cancers. There is a strong correlation between loss of 5hmC and cancer development but research to date indicates that loss of TET activity is associated with the cancer phenotype but it is not clear whether TET proteins function as tumor suppressors or oncogenes. While loss of TET1 and TET2 expression is associated with solid cancers, implying a tumor suppressor role, TET1 exhibits a clear oncogenic role in the context of genomic rearrangements such as in MLL-fusion rearranged leukemia. Interestingly, hypoxia increases global 5hmC levels and upregulates TET1 expression in a HIF1α-dependent manner. Recently, hypoxia-induced TET1 has been demonstrated to play another important role for regulating hypoxia-responsive gene expression and epithelial-mesenchymal transition (EMT) by serving as a transcription co-activator. Furthermore, hypoxia-induced TET1 also regulates glucose metabolism and hypoxia-induced EMT through enhancing the expression of insulin induced gene 1 (INSIG1). The roles and mechanisms of action of 5hmC and TET proteins in ES cell biology and during embryonic development, as well as in cancer biology, will be the main focus in this review.