TY - JOUR
T1 - Tumour hypoxia causes DNA hypermethylation by reducing TET activity
AU - Thienpont, Bernard
AU - Steinbacher, Jessica
AU - Zhao, Hui
AU - D'Anna, Flora
AU - Kuchnio, Anna
AU - Ploumakis, Athanasios
AU - Ghesquière, Bart
AU - Van Dyck, Laurien
AU - Boeckx, Bram
AU - Schoonjans, Luc
AU - Hermans, Els
AU - Amant, Frederic
AU - Kristensen, Vessela N
AU - Koh, Kian Peng
AU - Mazzone, Massimiliano
AU - Coleman, Mathew L
AU - Carell, Thomas
AU - Carmeliet, Peter
AU - Lambrechts, Diether
PY - 2016/9/1
Y1 - 2016/9/1
N2 - 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.
AB - 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.
U2 - 10.1038/nature19081
DO - 10.1038/nature19081
M3 - Article
C2 - 27533040
SN - 0028-0836
VL - 537
SP - 63
EP - 68
JO - Nature
JF - Nature
IS - 7618
ER -