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Oncotarget. 2015 Nov 10;6(35):37647-62. doi: 10.18632/oncotarget.6069.

Decrease of 5hmC in gastric cancers is associated with TET1 silencing due to with DNA methylation and bivalent histone marks at TET1 CpG island 3'-shore.

Author information

1
Epigenome Research Center, Genome Institute, KRIBB, Daejeon, Republic of Korea.
2
Department of Functional Genomics, Korea University of Science and Technology, Daejeon, Republic of Korea.
3
Department of Pathology, College of Medicine, Chungnam National University, Daejeon, Republic of Korea.
4
Department of Pathology, Seoul National University College of Medicine, Seoul, Republic of Korea.
5
Departments of Preventive Medicine, College of Medicine, Hanyang University, Seoul, Republic of Korea.

Abstract

Recent evidence has shown that the level of 5-hydroxymethylcytosine (5 hmC) in chromosomal DNA is aberrantly decreased in a variety of cancers, but whether this decrease is a cause or a consequence of tumorigenesis is unclear. Here we show that, in gastric cancers, the 5 hmC decrease correlates with a decrease in ten-eleven translocation 1 (TET1) expression, which is strongly associated with metastasis and poor survival in patients with gastric cancer. In gastric cancer cells, TET1-targeted siRNA induced a decrease in 5 hmC, whereas TET1 overexpression induced an increase in 5 hmC and reduced cell proliferation, thus correlating decreased 5 hmC with gastric carcinogenesis. We also report the epigenetic signatures responsible for regulating TET1 transcription. Methyl-CpG Binding Domain Sequencing and Reduced Representation Bisulfite Sequencing identified unique CpG methylation signatures at the CpG island 3'-shore region located 1.3 kb from the transcription start site of TET1 in gastric tumor cells but not in normal mucosa. The luciferase activity of constructs with a methylated 3'-shore sequence was greatly decreased compared with that of an unmethylated sequence in transformed gastric cancer cells. In gastric cancer cells, dense CpG methylation in the 3'-shore was strongly associated with TET1 silencing and bivalent histone marks. Thus, a decrease in 5 hmC may be a cause of gastric tumorigenesis owing to a decrease in TET1 expression through DNA methylation coupled with bivalent marks in the 3'-shore of TET1.

KEYWORDS:

3′-shore; 5-hydroxymethylcytosine; DNA methylation; TET1; bivalent mark; gastric cancer

PMID:
26462176
PMCID:
PMC4741955
DOI:
10.18632/oncotarget.6069
[Indexed for MEDLINE]
Free PMC Article

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