Tumour hypoxia causes DNA hypermethylation by reducing TET activity

Bernard Thienpont (), Jessica Steinbacher, Hui Zhao, Flora D’Anna, Anna Kuchnio, Athanasios Ploumakis, Bart Ghesquière, Laurien Van Dyck, Bram Boeckx, Luc Schoonjans, Els Hermans, Frederic Amant, Vessela N. Kristensen, Kian Peng Koh, Massimiliano Mazzone, Mathew L. Coleman, Thomas Carell, Peter Carmeliet and Diether Lambrechts ()
Additional contact information
Bernard Thienpont: Vesalius Research Center, VIB
Jessica Steinbacher: Center for Integrative Protein Science, Ludwig-Maximilians-Universität
Hui Zhao: Vesalius Research Center, VIB
Flora D’Anna: Vesalius Research Center, VIB
Anna Kuchnio: Vesalius Research Center, VIB
Athanasios Ploumakis: Institute of Cancer and Genomic Sciences, University of Birmingham
Bart Ghesquière: Vesalius Research Center, VIB
Laurien Van Dyck: Vesalius Research Center, VIB
Bram Boeckx: Vesalius Research Center, VIB
Luc Schoonjans: Vesalius Research Center, VIB
Els Hermans: Gynecologic Oncology, University Hospitals Leuven
Frederic Amant: Gynecologic Oncology, University Hospitals Leuven
Vessela N. Kristensen: Institute for Cancer Research, Oslo University Hospital Radiumhospitalet
Kian Peng Koh: and Stem Cell Institute Leuven
Massimiliano Mazzone: Vesalius Research Center, VIB
Mathew L. Coleman: Institute of Cancer and Genomic Sciences, University of Birmingham
Thomas Carell: Center for Integrative Protein Science, Ludwig-Maximilians-Universität
Peter Carmeliet: Vesalius Research Center, VIB
Diether Lambrechts: Vesalius Research Center, VIB

Nature, 2016, vol. 537, issue 7618, 63-68

Abstract: 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.

Date: 2016
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DOI: 10.1038/nature19081

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