Candidate gene-based studies have identified a handful of aberrant CpG DNA 
methylation events in prostate cancer. However, DNA methylation profiles have 
not been compared on a large scale between prostate tumor and normal prostate, 
and the mechanisms behind these alterations are unknown. In this study, we 
quantitatively profiled 95 primary prostate tumors and 86 benign adjacent 
prostate tissue samples for their DNA methylation levels at 26,333 CpGs 
representing 14,104 gene promoters by using the Illumina HumanMethylation27 
platform. A 2-class Significance Analysis of this data set revealed 5912 CpG 
sites with increased DNA methylation and 2151 CpG sites with decreased DNA 
methylation in tumors (FDR < 0.8%). Prediction Analysis of this data set 
identified 87 CpGs that are the most predictive diagnostic methylation 
biomarkers of prostate cancer. By integrating available clinical follow-up data, 
we also identified 69 prognostic DNA methylation alterations that correlate with 
biochemical recurrence of the tumor. To identify the mechanisms responsible for 
these genome-wide DNA methylation alterations, we measured the gene expression 
levels of several DNA methyltransferases (DNMTs) and their interacting proteins 
by TaqMan qPCR and observed increased expression of DNMT3A2, DNMT3B, and EZH2 in 
tumors. Subsequent transient transfection assays in cultured primary prostate 
cells revealed that DNMT3B1 and DNMT3B2 overexpression resulted in increased 
methylation of a substantial subset of CpG sites that showed tumor-specific 
increased methylation.