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Tumour hypoxia causes DNA hypermethylation by reducing TET activity

Author

Listed:
  • Bernard Thienpont

    (Vesalius Research Center, VIB
    Laboratory of Translational Genetics)

  • Jessica Steinbacher

    (Center for Integrative Protein Science, Ludwig-Maximilians-Universität)

  • Hui Zhao

    (Vesalius Research Center, VIB
    Laboratory of Translational Genetics)

  • Flora D’Anna

    (Vesalius Research Center, VIB
    Laboratory of Translational Genetics)

  • Anna Kuchnio

    (Vesalius Research Center, VIB
    Laboratory of Angiogenesis and Vascular Metabolism)

  • Athanasios Ploumakis

    (Institute of Cancer and Genomic Sciences, University of Birmingham)

  • Bart Ghesquière

    (Vesalius Research Center, VIB)

  • Laurien Van Dyck

    (Vesalius Research Center, VIB
    Laboratory of Translational Genetics)

  • Bram Boeckx

    (Vesalius Research Center, VIB
    Laboratory of Translational Genetics)

  • Luc Schoonjans

    (Vesalius Research Center, VIB
    Laboratory of Angiogenesis and Vascular Metabolism)

  • 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
    Akershus University Hospital and Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Postboks 1171, Blindern 0318 Oslo, Norway)

  • Kian Peng Koh

    (and Stem Cell Institute Leuven)

  • Massimiliano Mazzone

    (Vesalius Research Center, VIB
    Laboratory of Molecular Oncology and Angiogenesis)

  • 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
    Laboratory of Angiogenesis and Vascular Metabolism)

  • Diether Lambrechts

    (Vesalius Research Center, VIB
    Laboratory of Translational Genetics)

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.

Suggested Citation

  • 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 Ama, 2016. "Tumour hypoxia causes DNA hypermethylation by reducing TET activity," Nature, Nature, vol. 537(7618), pages 63-68, September.
  • Handle: RePEc:nat:nature:v:537:y:2016:i:7618:d:10.1038_nature19081
    DOI: 10.1038/nature19081
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    Cited by:

    1. Manju Padmasekar & Rajkumar Savai & Werner Seeger & Soni Savai Pullamsetti, 2021. "Exposomes to Exosomes: Exosomes as Tools to Study Epigenetic Adaptive Mechanisms in High-Altitude Humans," IJERPH, MDPI, vol. 18(16), pages 1-20, August.
    2. Weili Wang & Huizhen Zheng & Jun Jiang & Zhi Li & Dongpeng Jiang & Xiangru Shi & Hui Wang & Jie Jiang & Qianqian Xie & Meng Gao & Jianhong Chu & Xiaoming Cai & Tian Xia & Ruibin Li, 2022. "Engineering micro oxygen factories to slow tumour progression via hyperoxic microenvironments," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    3. Mei Luo & Lin Ye & Ruimin Chang & Youqiong Ye & Zhao Zhang & Chunjie Liu & Shengli Li & Ying Jing & Hang Ruan & Guanxiong Zhang & Yi He & Yaoming Liu & Yu Xue & Xiang Chen & An-Yuan Guo & Hong Liu & L, 2022. "Multi-omics characterization of autophagy-related molecular features for therapeutic targeting of autophagy," Nature Communications, Nature, vol. 13(1), pages 1-17, December.

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