EZH2 is part of the PRC2 polycomb repressive complex that is overexpressed in 
multiple cancer types and has been implicated in prostate cancer initiation and 
progression. Here, we identify EZH2 as a target of the MYC oncogene in prostate 
cancer and show that MYC coordinately regulates EZH2 through transcriptional and 
post-transcriptional means. Although prior studies in prostate cancer have 
revealed a number of possible mechanisms of EZH2 upregulation, these changes 
cannot account for the overexpression EZH2 in many primary prostate cancers, nor 
in most cases of high grade PIN. We report that upregulation of Myc in the mouse 
prostate results in overexpression of EZH2 mRNA and protein which coincides with 
reductions in miR-26a and miR-26b, known regulators of EZH2 in some non-prostate 
cell types, albeit not in others. Further, in human prostate cancer cells, Myc 
negatively regulates miR-26a and miR-26b via direct binding to their parental 
Pol II gene promoters, and forced overexpression of miR-26a and miR-26b in 
prostate cancer cells results in decreased EZH2 levels and suppressed 
proliferation. In human clinical samples, miR-26a and miR-26b are downregulated 
in most primary prostate cancers. As a separate mechanism of EZH2 mRNA 
upregulation, we find that Myc binds directly to and activates the transcription 
of the EZH2 promoter. These results link two major pathways in prostate cancer 
by providing two additional and complementary Myc-regulated mechanisms by which 
EZH2 upregulation occurs and is enforced during prostatic carcinogenesis. 
Further, the results implicate EZH2-driven mechanisms by which Myc may stimulate 
prostate tumor initiation and disease progression.