English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Global: Zendy Plus annual

Presents the access of premium content as premium feature

Premium Content

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Global: Zendy Tools annual

Global: Zendy Free Plan

Global: Zendy Tools monthly

Global: Zendy Plus monthly

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 expression status and measures of PCa progression. As differential methylation profiles and TET2 expression are associated with advanced PCa, further investigation of these specialized TET2 targets may provide important insights into patterns of carcinogenic gene dysregulation.    Electronic supplementary material  The online version of this article (10.1186/s13148-019-0651-z) contains supplementary material, which is available to authorized users.

Exploring targets of TET2-mediated methylation reprogramming as potential discriminators of prostate cancer progression