Hypoxia and epigenetic modifications
Epigenetic modifications such as DNA methylation are central to the regulation of gene transcription and impact genome stability as well as development. The enzymes responsible for DNA demethylation were only identified a few years ago. Indeed, the discovery of the ten-eleven translocation (TET) family of enzymes capable of 5-methylcytosine oxidation has greatly advanced our understanding of DNA demethylation. In cancer, DNA methylation is deregulated and hyper-methylation of tumour suppressor gene promoters confers growth advantages to cancer cells. The conversion of 5-methylcytosine to 5-hydroxymethylcytosine by TET enzymes requires oxygen whereas hypoxia is common in cancer, suggesting a potential synergistic effect. In addition, hypoxia induces the activity of HIF transcription factors, which alter gene expression in cells to cope with hypoxia. However, the association of HIF factors with the epigenome is currently unknown. Furthermore, murine breast tumours become hyper-methylated when rendered hypoxic, whereas vessel normalisation rescues this effect. The primary objective of the EU-funded CHAMELEO (Cellular hypoxia alters DNA methylation through loss of epigenome oxidation) project was to investigate the influence of hypoxia on the epigenome and the resulting phenotypic response in cancer. Researchers demonstrated that tumour hypoxia reduced the activity of oxygen-dependent TET enzymes. This was independent of hypoxia-associated alterations in TET gene expression, basal metabolism, HIF activity or nuclear reactive oxygen species. The loss of TET activity depended solely on oxygen shortage and increased the hyper-methylation of gene promoters. Similar observations on the methylation of gene promoters were made in patient tumour samples where genes involved in DNA repair, cell cycle regulation, angiogenesis and metastasis were frequently involved. Furthermore, this suggested a clonal selection of hyper-methylation events to support growth and metastasis. Collectively, the findings of the CHAMELEO study support the regulatory role of tumour hypoxia on DNA methylation. Importantly, they suggest that strategies destined to normalise intra-tumour oxygen levels will reverse epigenetic changes and might modulate cancer cell properties.
Keywords
Hypoxia, cancer, DNA methylation, TET, CHAMELEO
