Abstract
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.
Highlights
EZH2 is a histone lysine methyltransferase that is part of the PRC2 polycomb repressive complex
Myc overexpression in the prostate induces the morphologically distinguishing features of prostatic intraepithelial neoplasia (PIN), including nuclear and nucleolar enlargement, an increase in mitotic figures, as well as widespread chromatin remodeling. Using these mice for immunohistochemical staining, we observed that the expression of EZH2 protein was barely detectable in control non-transgenic littermate mice, but that levels were markedly upregulated in PIN lesions in the LoMYC mice (Fig. 1A)
Two of these mechanisms (EZH2 amplification and miR-101 deletion) are encountered more frequently in advanced and castrate resistant prostate cancers than in primary untreated prostate cancers, and ETS family gene fusions and ERG protein overexpression are rarely seen in isolated PIN lesions or PIN lesions associated with ERG-negative carcinomas [34]
Summary
EZH2 is a histone lysine methyltransferase that is part of the PRC2 polycomb repressive complex. It catalyzes the tri-methylation of histone 3 on lysine 27 (H3K27me3), which is involved in chromatin remodeling and the silencing of genes, including homeobox genes involved in differentiation [1-4]. Prior studies indicated that at least three separate mechanisms could result in EZH2 upregulation in prostate cancer. The original study by Varambally et al documented upregulation of EZH2 in the majority of all prostate cancer cases, as well as in the majority of all high grade PIN, a key prostate cancer precursor lesion [6]. We hypothesized that additional mechanisms are likely operative that induce EZH2 upregulation in prostate cancer, at least during the early phases of the disease
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