Methylomics analysis identifies ZNF671 as an epigenetically repressed novel tumor suppressor and a potential non-invasive biomarker for the detection of urothelial carcinoma.
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.
['Yeh|Chia-Ming|CM|', 'Chen|Pi-Che|PC|', 'Hsieh|Hsiao-Yen|HY|', 'Jou|Yeong-Chin|YC|', 'Lin|Chang-Te|CT|', 'Tsai|Ming-Hsuan|MH|', 'Huang|Wen-Yu|WY|', 'Wang|Yi-Ting|YT|', 'Lin|Ru-Inn|RI|', 'Chen|Szu-Shan|SS|', 'Tung|Chun-Liang|CL|', 'Wu|Shu-Fen|SF|', 'Chang|D Ching|DC|', 'Shen|Cheng-Huang|CH|', 'Hsu|Cheng-Da|CD|', 'Chan|Michael W Y|MW|']
D000818:Animals D014408:Biomarkers, Tumor D002295:Carcinoma, Transitional Cell D045744:Cell Line, Tumor D019175:DNA Methylation D004273:DNA, Neoplasm D044127:Epigenesis, Genetic D005260:Female D015972:Gene Expression Regulation, Neoplastic D006801:Humans D008297:Male D008807:Mice, Inbred BALB C D008819:Mice, Nude D008875:Middle Aged D020133:Reverse Transcriptase Polymerase Chain Reaction D017422:Sequence Analysis, DNA D014183:Transplantation, Heterologous D047368:Tumor Burden D025521:Tumor Suppressor Proteins D001749:Urinary Bladder Neoplasms
ZNF671 urothelial carcinoma urine DNA methylation