Abstract B075: The role of TET1 and hydroxymethylation in high-risk prostate cancer

• Published in: Cancer research (Chicago, Ill.) Vol. 78; no. 16_Supplement; p. B075
• Main Authors: Smeets, Elien, Spans, Lien, Prekovic, Stefan, Broeck, Thomas Van den, Moris, Lisa, Gevaert, Thomas, Helsen, Christine, Joniau, Steven, Claessens, Frank
• Format: Journal Article
• Language: English
• Published: 15.08.2018
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.PRCA2017-B075

The Ten-eleven translocation (TET) proteins are dioxygenases that catalyze the oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) as part of the DNA demethylation pathway. Gene silencing through cytosine methylation contributes to cancer formation, but how hydroxymethylation affects gene expression is largely unknown. In this work, TET1 and genomic hydroxymethylation were investigated in a high-risk prostate cancer cohort for which exome sequencing data are available (1). Immunohistochemical analysis of tumor versus nontumor prostate biopsies from high-risk prostate cancer showed a strong reduction of genome-wide 5hmC and milder but still significant reduction of 5mC levels in prostate cancer tissue compared to control tissue. Copy number analysis of high-risk prostate cancer showed a loss of the TET1 genomic region in 6 out of 39 samples of our cohort. As expected, the mRNA levels of TET1 were decreased in these tumor samples. Recently, an alternative promoter of TET1 was discovered. This promoter generates a novel isoform lacking the CXXC-domain, which is called TET1ALT (2). We therefore performed functional analyses of the two TET1 promoters in prostate cancer cells. Interestingly, the promoter controlling expression of the endogenous full-length TET1 is less active in prostate cancer cell line PC-3, while the alternative promoter generating TET1ALT is more active in these cells. This is shown by luciferase constructs driven by the two promoter regions. In conclusion, our findings indicate that there is a drop in (hydroxy)methylation levels in high-risk prostate cancer that correlates with decreased TET1 expression levels and in some cases by a copy number loss of TET1. We are currently working on a more detailed analysis of TET1 promoter usage and control. This will unravel the regulation of hydroxymethylation in prostate cancer, which is crucial for the understanding of prostate cancer development and progression. References: 1. Spans L, Van den Broeck T, Smeets E, et al. Genomic and epigenomic analysis of high-risk prostate cancer reveals changes in hydroxymethylation and TET1. Oncotarget 2016;7(17):24326-38. 2. Good CR, Madzo J, Patel B, et al. A novel isoform of TET1 that lacks a CXXC domain is overexpressed in cancer. Nucleic Acids Res 2017;45(14):8269-81. Citation Format: Elien Smeets, Lien Spans, Stefan Prekovic, Thomas Van den Broeck, Lisa Moris, Thomas Gevaert, Christine Helsen, Steven Joniau, Frank Claessens. The role of TET1 and hydroxymethylation in high-risk prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B075.