Concepts of epigenetics in prostate cancer development

Abstract

Substantial evidence now supports the view that epigenetic changes have a role in the development of human prostate cancer. Analyses of the patterns of epigenetic alteration are providing important insights into the origin of this disease and have identified specific alterations that may serve as useful diagnostic and prognostic biomarkers. Examination of cancer methylation patterns supports a stem cell origin of prostate cancer. It is well established that methylation of GSTpi is a marker of prostate cancer, and global patterns of histone marking appear to be linked to cancer prognosis with levels of acetylated histones H3K9, H3K18, and H4K12, and of dimethylated H4R3 and H3K4, dividing low-grade prostate cancer (Gleason 6 or less) into two prognostically separate groups. Elevated levels of several components of the polycomb group protein complex, EZH2, BMI1, and RING1, can also act as biomarkers of poor clinical outcome. Many components of the epigenetic machinery, including histone deacetylase (whose expression level is linked to the TMPRSS2:ERG translocation) and the histone methylase EZH2, are potential therapeutic targets. The recent discovery of the role of small RNAs in governing the epigenetic status of individual genes offers exciting new possibilities in therapeutics and chemoprevention.

Figure 1

Working model for transition of bivalent stem cell chromatin to inactive chromatin during cancer development. In stem cells, chromatin exists in a bivalent state characterised by the absence of DNA methylation and the presence of both activating (e.g., H3K4me2) and inactivating (H3K27me3) markers. During cancer development, it is proposed that recruitment of DMNTs through EZH2 causes methylation of DNA. The inactive chromatin is characterised by the markers H3K9me2, H3K9me3, and H3K27me3. Model taken from the data presented by Ohm et al (2007) and Schlesinger et al (2007).