Hypermethylation of the promoters of tumour suppressor genes represses transcription of these genes, conferring growth advantages to cancer cells. How these changes arise is poorly understood. Here we show that the activity of oxygen-dependent ten-eleven translocation (TET) enzymes is reduced by tumour hypoxia in human and mouse cells. TET enzymes catalyse DNA demethylation through 5-methylcytosine oxidation. This reduction in activity occurs independently of hypoxia-associated alterations in TET expression, proliferation, metabolism, hypoxia-inducible factor activity or reactive oxygen species, and depends directly on oxygen shortage. Hypoxia-induced loss of TET activity increases hypermethylation at gene promoters in vitro. In patients, tumour suppressor gene promoters are markedly more methylated in hypoxic tumour tissue, independent of proliferation, stromal cell infiltration and tumour characteristics. Our data suggest that up to half of hypermethylation events are due to hypoxia, with these events conferring a selective advantage. Accordingly, increased hypoxia in mouse breast tumours increases hypermethylation, while restoration of tumour oxygenation abrogates this effect. Tumour hypoxia therefore acts as a novel regulator of DNA methylation. Tumours are epigenetically distinct from their tissue of origin, frequently showing increased DNA methylation of tumour suppressor gene promoters, but how these changes arise is poorly understood. Here, Diether Lambrechts and colleagues report that tumour hypoxia, pervasive in many solid tumours, reduces the activity of the oxygen-dependent ten-eleven translocation (TET) enzymes, which catalyse DNA demethylation through 5-methylcytosine oxidation. They show that oxygen is an important co-factor for TET activity, and hypoxia-induced loss of TET activity increases hypermethylation at gene promoters in vitro and at tumour suppressor genes in hypoxic tumours. The authors propose that tumour hypoxia directly reduces TET activity, leading to changes in DNA methylation and silencing gene expression. Countering hypermethylation by inhibiting DNA methylation or by normalizing tumour blood supply may therefore be of therapeutic benefit.

Tumour hypoxia causes DNA hypermethylation by reducing TET activity