Investigating novel targets of DNA methylation for the early detection of prostate cancer

Abstract

Prostate cancer is an escalating international health problem. It is the most common non- cutaneous malignancy and the second leading cause of cancer related deaths in men in the Western world. Like many other cancers, metastases are the main cause of prostate cancer- related death. However, it is not clear what molecular events are responsible for the progression of prostate cancer to a lethal form of the disease. Therefore, there is an urgent need to identify aggressive tumours while in their early stages and confined within the prostate capsule. The objective of this study was to investigate methylation of novel targets in prostate cancer to facilitate a greater understanding of the pathogenesis of the disease and to contribute towards a prostate cancer methylation signature that could be used in early detection and in addition provide valuable prognostic information. Promoter hypermethylation is recognised as a significant force in human carcinogenesis, in addition to more conventional mechanisms of gene inactivation. It is a frequent event in many human cancers and can occur at an early stage in cancer development and in a tumour-type specific manner. CpG methylation leads to gene silencing by blocking transcription factor binding and/or attracting methyl-specific binding proteins that interact with histone deacetylases (HDACs) to promote chromatin condensation, thus rendering the DNA inaccessible to the transcriptional apparatus. We developed an in silico strategy to globally identify potential targets of promoter hypermethylation in prostate cancer by screening over 800 genes, that were reported as down-regulated in prostate cancer, for a 5’ CpG island (the target of DNA methylation). An advantage to this approach was that different pathways and families of genes could be simultaneously evaluated. The net result was a virtual bank of 338 potential targets of methylation in prostate cancer.