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Fig. 2 | Clinical Epigenetics

Fig. 2

From: Tracing TET1 expression in prostate cancer: discovery of malignant cells with a distinct oncogenic signature

Fig. 2

Analysis of TET1 promoter methylation and expression in PCa and NOR tissue, and in PCa cell lines. A Based on the transcriptome data (FPKM: fragments per kilobase per million mapped reads) and methylome data (ß-values) of the Cancer Genome Atlas, we performed correlation analyses between TET1 expression (E) and TET1 methylation (M) at 30 CpG probes in 35 NOR and 341 PCa (A.1, Correlation of methylation with expression (M/E), n: significant negative correlation, p: significant positive correlation, Spearman). Comparison of ß-values at 30 CpG probes in PCa (341) and NOR (35) revealed 22 differentially methylated CpG sites in PCa (A.1, Diff. Methylation, 18 red up-arrows: 18 significantly hypermethylated sites in PCa, four green down-arrows: four significantly hypomethylated sites in PCa, Mann–Whitney U test). The impact of differential methylation at these 22 CpG sites on TET1 expression was assessed according to the correlation of M/E in PCa (A.1, Impact of M on E, down arrows: downregulation, up arrows: upregulation). Methylation at TET1_cg02952701 showed the strongest correlation with TET1 expression in both NOR (A.2) and PCa (A.3); B In LNCaP cells, TET1_cg02952701 was hypermethylated (B.1), and TET1-mRNA and TET1-protein were downregulated (B.2 and B.3). In DU145 and PC3 cells, TET1_cg02952701 was hypomethylated (B.1), and TET1 mRNA and TET1 protein were expressed (B.2 and B.3); C based on TET1 expression, we categorized the PCa cohort into three groups: low (expression < 40th percentile, n = 136), moderate (≥ 40th and ≤ 85th percentile, n = 154), and high (> 85th percentile, n = 51) (C.1). Accordingly, the TET1-high group showed the least methylation in TET1_cg02952701 and the TET1-low group showed the most methylation (C.2). Comparison of ß-values at 30 CpG probes in TET1-high PCa versus TET1-low PCa revealed nine differentially methylated CpG-sites in TET1-high PCa (C.3, Diff. Methylation, four green arrows: four significantly hypomethylated sites, five red arrows: five significantly hypermethylated sites). The four hypomethylated CpG sites in the promoter were significantly negatively correlated with TET1 expression and thus, led to TET1 upregulation. Three out of five hypermethylated CpG sites in the 5′-UTR and gene body were significantly positively correlated with TET1 expression and thus also led to TET1 upregulation (C.3, Correlation M/E, n: significant negative correlation, p: significant positive correlation, Spearman; Impact of M on E, up arrows: upregulation). Grouping of PCa by tumor stage and Gleason score revealed that TET1-high PCa occurred more frequently in advanced stages of PCa (C.4)

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