Volume 26, No 1, Jan 2016
ISSN: 1001-0602
EISSN: 1748-7838 2018
impact factor 17.848*
(Clarivate Analytics, 2019)
Volume 26 Issue 1, January 2016: 103-118
ORIGINAL ARTICLES
Loss of 5-hydroxymethylcytosine is linked to gene body hypermethylation in kidney cancer
Ke Chen1,*, Jing Zhang2,9,*, Zhongqiang Guo3,10,*, Qin Ma1, Zhengzheng Xu1, Yuanyuan Zhou1, Zhiying Xu1, Zhongwu Li4, Yiqiang Liu4, Xiongjun Ye5, Xuesong Li3, Bifeng Yuan6, Yuwen Ke2, Chuan He7, Liqun Zhou3, Jiang Liu2,8 and Weimin Ci1
1Key Laboratory of Genomic and Precision Medicine, Beijing 100101, China
2Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
3Department of Urology, Peking University First Hospital, Beijing, 100034, China
4Key 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
5Department of Urology, Peking University People's Hospital, Beijing 100034, China
6Key Laboratory of Analytical Chemistry for Biology and Medicine (Ministry of Education), Department of Chemistry, Wuhan University, Wuhan, Hubei 430072, China
7Institute for Genomics and Systems Biology and Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA
8Collaborative Innovation Center of Genetics and Development, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
9Current address: Institute for Cancer Genetics, Irving Cancer Research Center, Columbia University, New York, NY 10032, USA
10Current address: Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, China
Correspondence: Weimin Ci, E-mail: ciwm@big.ac.cn; Jiang Liu, E-mail: liuj@big.ac.cn; Liqun Zhou,(zhoulqmail@china.com)
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.
10.1038/cr.2015.150
FULL TEXT | PDF
Browse 2786
