title: Tumour hypoxia causes DNA hypermethylation by reducing TET activity.
abstract: 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.
authors.affiliation: Vesalius Research Center, VIB, Leuven, Belgium.|Laboratory of Translational Genetics, Department of Oncology, KU Leuven, Leuven, Belgium.
authors.forename: Bernard
authors.initials: B
authors.lastname: Thienpont
authors.affiliation: Department für Chemie und Pharmazie, Ludwig-Maximilians-Universität, München, Germany.
authors.forename: Jessica
authors.initials: J
authors.lastname: Steinbacher
authors.affiliation: Vesalius Research Center, VIB, Leuven, Belgium.|Laboratory of Translational Genetics, Department of Oncology, KU Leuven, Leuven, Belgium.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Vesalius Research Center, VIB, Leuven, Belgium.|Laboratory of Translational Genetics, Department of Oncology, KU Leuven, Leuven, Belgium.
authors.forename: Flora
authors.initials: F
authors.lastname: D'Anna
authors.affiliation: Vesalius Research Center, VIB, Leuven, Belgium.|Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven, Belgium.
authors.forename: Anna
authors.initials: A
authors.lastname: Kuchnio
authors.affiliation: Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
authors.forename: Athanasios
authors.initials: A
authors.lastname: Ploumakis
authors.affiliation: Vesalius Research Center, VIB, Leuven, Belgium.
authors.forename: Bart
authors.initials: B
authors.lastname: Ghesquière
authors.affiliation: Vesalius Research Center, VIB, Leuven, Belgium.|Laboratory of Translational Genetics, Department of Oncology, KU Leuven, Leuven, Belgium.
authors.forename: Laurien
authors.initials: L
authors.lastname: Van Dyck
authors.affiliation: Vesalius Research Center, VIB, Leuven, Belgium.|Laboratory of Translational Genetics, Department of Oncology, KU Leuven, Leuven, Belgium.
authors.forename: Bram
authors.initials: B
authors.lastname: Boeckx
authors.affiliation: Vesalius Research Center, VIB, Leuven, Belgium.|Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven, Belgium.
authors.forename: Luc
authors.initials: L
authors.lastname: Schoonjans
authors.affiliation: Gynecologic Oncology, University Hospitals Leuven, Department of Oncology, KU Leuven, Leuven, Belgium.
authors.forename: Els
authors.initials: E
authors.lastname: Hermans
authors.affiliation: Gynecologic Oncology, University Hospitals Leuven, Department of Oncology, KU Leuven, Leuven, Belgium.
authors.forename: Frederic
authors.initials: F
authors.lastname: Amant
authors.affiliation: Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway.
authors.forename: Vessela N
authors.initials: VN
authors.lastname: Kristensen
authors.affiliation: Department of Development and Regeneration, and Stem Cell Institute Leuven, KU Leuven, Leuven, Belgium.
authors.forename: Kian
authors.initials: K
authors.lastname: Peng Koh
authors.affiliation: Vesalius Research Center, VIB, Leuven, Belgium.|Laboratory of Molecular Oncology and Angiogenesis, Department of Oncology, KU Leuven, Leuven, Belgium.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Mazzone
authors.affiliation: Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
authors.forename: Mathew
authors.initials: M
authors.lastname: Coleman
authors.affiliation: Department für Chemie und Pharmazie, Ludwig-Maximilians-Universität, München, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Carell
authors.affiliation: Vesalius Research Center, VIB, Leuven, Belgium.|Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
authors.affiliation: Vesalius Research Center, VIB, Leuven, Belgium.|Laboratory of Translational Genetics, Department of Oncology, KU Leuven, Leuven, Belgium.
authors.forename: Diether
authors.initials: D
authors.lastname: Lambrechts
mesh_terms: D044503:5-Methylcytosine / Q000378:metabolism; D000818:Animals; D049109:Cell Proliferation; D019175:DNA Methylation / Q000187:drug effects / Q000235:genetics; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D049308:Dioxygenases; D005260:Female; D020868:Gene Silencing / Q000187:drug effects; D016147:Genes, Tumor Suppressor; D006801:Humans; D008297:Male; D015674:Mammary Neoplasms, Animal / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D006899:Mixed Function Oxygenases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D010100:Oxygen / Q000378:metabolism* / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D017154:Stromal Cells / Q000473:pathology; D000072258:Tumor Hypoxia / Q000187:drug effects / Q000235:genetics / Q000502:physiology*
chemical_list: D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D044503:5-Methylcytosine; D006899:Mixed Function Oxygenases; C462539:TET1 protein, human; D049308:Dioxygenases; C551914:Tet2 protein, mouse; D010100:Oxygen