Role of hydroxymethylation as an epigenetic mark in prostate cancer biology

Because of the low recurrence rates of genomic mutations in prostate cancer, epigenetics is again at the forefront of our efforts to understand the etiology of this disease. Hydroxymethylcytosine (5hmC) is a new epigenetic mark for which little data exists in prostate cancer. During whole exome sequencing of high risk prostate cancer, we discovered mutations in TET1, which is one of three enzymes responsible for the hydroxylation of methylcytosines. In addition, we found indications of an inverse correlation between TET1 expression level and the risk of developing metastatic PCa. This clearly indicates that TET1 (and by extension 5hmC) has an important role in prostate cancer biology. This project will provide the first maps of cancer-specific changes in 5hmC modifications in prostate cancer by comparing its genome wide distribution in cancer versus normal adjacent tissues. We will identify the mechanisms that control 5hmC homeostasis, as well as the gene programs that are controlled by it. To this end, the expression of genes in the vicinity of the largest changes in 5hmC will be investigated in cohorts of clinical samples, as well as in our cellular models. Undoubtedly, this will provide an important new level of insight in the epigenetic control of high risk prostate cancer biology.