Background Global DNA methylation alterations are hallmarks of cancer. The tumor-suppressive TET enzymes, which are involved in DNA demethylation, are decreased in prostate cancer (PCa); in particular, TET2 is specifically targeted by androgen-dependent mechanisms of repression in PCa and may play a central role in carcinogenesis. Thus, the identification of key genes targeted by TET2 dysregulation may provide further insight into cancer biology. Results Using a CRISPR/Cas9-derived TET2 -knockout prostate cell line, and through whole-transcriptome and whole-methylome sequencing, we identified seven candidate genes— ASB2 , ETNK2 , MEIS2 , NRG1 , NTN1 , NUDT10 , and SRPX —exhibiting reduced expression and increased promoter methylation, a pattern characteristic of tumor suppressors. Decreased expression of these genes significantly discriminates between recurrent and non-recurrent prostate tumors from the Cancer Genome Atlas (TCGA) cohort ( n = 423), and ASB2 , NUDT10 , and SRPX were significantly correlated with lower recurrence-free survival in patients by Kaplan-Meier analysis. ASB2 , MEIS2 , and SRPX also showed significantly lower expression in high-risk Gleason score 8 tumors as compared to low or intermediate risk tumors, suggesting that these genes may be particularly useful as indicators of PCa progression. Furthermore, methylation array probes in the TCGA dataset, which were proximal to the highly conserved, differentially methylated sites identified in our TET2 -knockout cells, were able to significantly distinguish between matched prostate tumor and normal prostate tissues ( n = 50 pairs). Except ASB2 , all genes exhibited significantly increased methylation at these probes, and methylation status of at least one probe for each of these genes showed association with measures of PCa progression such as recurrence, stage, or Gleason score. Since ASB2 did not have any probes within the TET2 -knockout differentially methylated region, we validated ASB2 methylation in an independent series of matched tumor-normal samples ( n = 19) by methylation-specific qPCR, which revealed concordant and significant increases in promoter methylation within the TET2 -knockout site. Conclusions Our study identifies seven genes governed by TET2 loss in PCa which exhibit an association between their methylation and ...

BackgroundDespite the significant global loss of DNA hydroxymethylation marks in prostate cancer tissues, the locus-specific role of hydroxymethylation in prostate tumorigenesis is unknown. We characterized hydroxymethylation and methylation marks by performing whole-genome next-generation sequencing in representative normal and prostate cancer-derived cell lines in order to determine functional pathways and key genes regulated by these epigenomic modifications in cancer.ResultsOur cell line model shows disruption of hydroxymethylation distribution in cancer, with global loss and highly specific gain in promoter and CpG island regions. Significantly, we observed locus-specific retention of hydroxymethylation marks in specific intronic and intergenic regions which may play a novel role in the regulation of gene expression in critical functional pathways, such as BARD1 signaling and steroid hormone receptor signaling in cancer. We confirm a modest correlation of hydroxymethylation with expression in intragenic regions in prostate cancer, while identifying an original role for intergenic hydroxymethylation in differentially expressed regulatory pathways in cancer. We also demonstrate a successful strategy for the identification and validation of key candidate genes from differentially regulated biological pathways in prostate cancer.ConclusionsOur results indicate a distinct function for aberrant hydroxymethylation within each genomic feature in cancer, suggesting a specific and complex role for the deregulation of hydroxymethylation in tumorigenesis, similar to methylation. Subsequently, our characterization of key cellular pathways exhibiting dynamic enrichment patterns for methylation and hydroxymethylation marks may allow us to identify differentially epigenetically modified target genes implicated in prostate cancer tumorigenesis.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-016-0195-4) contains supplementary material, which is available to authorized users.