Methylomics analysis identifies ZNF671 as an epigenetically repressed novel tumor suppressor and a potential non-invasive biomarker for the detection of urothelial carcinoma
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Chia-Ming Yeh1,2,*, Pi-Che Chen3,*, Hsiao-Yen Hsieh2,5, Yeong-Chin Jou3, Chang-Te Lin3, Ming-Hsuan Tsai1, Wen-Yu Huang1,2, Yi-Ting Wang1,2, Ru-Inn Lin1,6, Szu-Shan Chen1,2, Chun-Liang Tung4, Shu-Fen Wu1,2, De-Ching Chang1,2, Cheng-Huang Shen3, Cheng-Da Hsu5 and Michael W.Y. Chan1,2,*
1 Department of Life Science, National Chung Cheng University, Min-Hsiung, Chia-Yi, Taiwan
2 Institute of Molecular Biology, National Chung Cheng University, Min-Hsiung, Chia-Yi, Taiwan
3 Department of Urology, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chia-Yi, Taiwan
4 Department of Pathology, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chia-Yi, Taiwan
5 Department of Medical Research, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chia-Yi, Taiwan
6 Departments of Radiation Oncology, Buddhist Dalin Tzu Chi General Hospital, Chia Yi, Taiwan
* These authors have contributed equally to this work
Michael W.Y. Chan, email:
Keywords: urothelial carcinoma, DNA methylation, urine, ZNF671
Received: April 03, 2015 Accepted: July 16, 2015 Published: July 22, 2015
The molecular mechanism underlying the lethal phenomenon of urothelial carcinoma (UC) tumor recurrence remains unresolved. Here, by methylation microarray, we identified promoter methylation of the zinc-finger protein gene, ZNF671 in bladder UC tumor tissue samples, a finding that was independently validated by bisulphite pyrosequencing in cell lines and tissue samples. Subsequent assays including treatment with epigenetic depressive agents and in vitro methylation showed ZNF671 methylation to result in its transcriptional repression. ZNF671 re-expression in UC cell lines, via ectopic expression, inhibited tumor growth and invasion, in possible conjunction with downregulation of cancer stem cell markers (c-KIT, NANOG, OCT4). Clinically, high ZNF671 methylation in UC tumor tissues (n=96; 63 bladder, 33 upper urinary tract) associated with tumor grade and poor locoregional disease-free survival. Quantitative MSP analysis in a training (n=97) and test (n=61) sets of voided urine samples from bladder UC patients revealed a sensitivity and specificity of 42%-48% and 89%-92.8%, respectively, for UC cancer detection. Moreover, combining DNA methylation of ZNF671 and 2 other genes (IRF8 and sFRP1) further increased the sensitivity to 96.2%, suggesting a possible three-gene UC biomarker. In summary, ZNF671, an epigenetically silenced novel tumor suppressor, represents a potential predictor for UC relapse and non-invasive biomarker that could assist in UC clinical decision-making.
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