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Cell Res. 2016 Jan;26(1):103-18. doi: 10.1038/cr.2015.150. Epub 2015 Dec 18.

Loss of 5-hydroxymethylcytosine is linked to gene body hypermethylation in kidney cancer.

Chen K1, Zhang J2,3, Guo Z4,5, Ma Q1, Xu Z1, Zhou Y1, Xu Z1, Li Z6, Liu Y6, Ye X7, Li X4, Yuan B8, Ke Y2, He C9, Zhou L4, Liu J2,10, Ci W1.

Author information

1
Key Laboratory of Genomic and Precision Medicine, China Gastrointestinal Cancer Research Center, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.
2
Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.
3
Current address: Institute for Cancer Genetics, Irving Cancer Research Center, Columbia University, New York, NY 10032, USA.
4
Department of Urology, Peking University First Hospital, Beijing, 100034, China.
5
Current address: Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, China.
6
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University School of Oncology, Peking University Cancer Hospital and Institute, Beijing 100142, China.
7
Department of Urology, Peking University People's Hospital, Beijing 100034, China.
8
Key Laboratory of Analytical Chemistry for Biology and Medicine (Ministry of Education), Department of Chemistry, Wuhan University, Wuhan, Hubei 430072, China.
9
Institute for Genomics and Systems Biology and Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA.
10
Collaborative Innovation Center of Genetics and Development, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.

Abstract

Both 5-methylcytosine (5mC) and its oxidized form 5-hydroxymethylcytosine (5hmC) have been proposed to be involved in tumorigenesis. Because the readout of the broadly used 5mC mapping method, bisulfite sequencing (BS-seq), is the sum of 5mC and 5hmC levels, the 5mC/5hmC patterns and relationship of these two modifications remain poorly understood. By profiling real 5mC (BS-seq corrected by Tet-assisted BS-seq, TAB-seq) and 5hmC (TAB-seq) levels simultaneously at single-nucleotide resolution, we here demonstrate that there is no global loss of 5mC in kidney tumors compared with matched normal tissues. Conversely, 5hmC was globally lost in virtually all kidney tumor tissues. The 5hmC level in tumor tissues is an independent prognostic marker for kidney cancer, with lower levels of 5hmC associated with shorter overall survival. Furthermore, we demonstrated that loss of 5hmC is linked to hypermethylation in tumors compared with matched normal tissues, particularly in gene body regions. Strikingly, gene body hypermethylation was significantly associated with silencing of the tumor-related genes. Downregulation of IDH1 was identified as a mechanism underlying 5hmC loss in kidney cancer. Restoring 5hmC levels attenuated the invasion capacity of tumor cells and suppressed tumor growth in a xenograft model. Collectively, our results demonstrate that loss of 5hmC is both a prognostic marker and an oncogenic event in kidney cancer by remodeling the DNA methylation pattern.

PMID:
26680004
PMCID:
PMC4816137
DOI:
10.1038/cr.2015.150
[Indexed for MEDLINE]
Free PMC Article

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