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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.

journal_name

Nature

journal_title

Nature

authors

Thienpont B,Steinbacher J,Zhao H,D'Anna F,Kuchnio A,Ploumakis A,Ghesquière B,Van Dyck L,Boeckx B,Schoonjans L,Hermans E,Amant F,Kristensen VN,Peng Koh K,Mazzone M,Coleman M,Carell T,Carmeliet P,Lambrechts D

doi

10.1038/nature19081

subject

Has Abstract

pub_date

2016-09-01 00:00:00

pages

63-68

issue

7618

eissn

0028-0836

issn

1476-4687

journal_volume

537

pub_type

杂志文章

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