Cooperation between Polycomb and androgen receptor during oncogenic transformation

Abstract

Androgen receptor (AR) is a hormone-activated transcription factor that plays important roles in prostate development and function, as well as malignant transformation. The downstream pathways of AR, however, are incompletely understood. AR has been primarily known as a transcriptional activator inducing prostate-specific gene expression. Through integrative analysis of genome-wide AR occupancy and androgen-regulated gene expression, here we report AR as a globally acting transcriptional repressor. This repression is mediated by androgen-responsive elements (ARE) and dictated by Polycomb group protein EZH2 and repressive chromatin remodeling. In embryonic stem cells, AR-repressed genes are occupied by EZH2 and harbor bivalent H3K4me3 and H3K27me3 modifications that are characteristic of differentiation regulators, the silencing of which maintains the undifferentiated state. Concordantly, these genes are silenced in castration-resistant prostate cancer rendering a stem cell–like lack of differentiation and tumor progression. Collectively, our data reveal an unexpected role of AR as a transcriptional repressor inhibiting non-prostatic differentiation and, upon excessive signaling, resulting in cancerous dedifferentiation.

Androgens and androgen receptor signaling in prostate tumorigenesis

“…In addition to its capacity as an epigenetic modifier, EZH2 was recently reported to function as an AR coactivator, although its coactivator activity is dependent on AKT-mediated phosphorylation of EZH2 (Xu et al 2012). Using ChIP-seq, EZH2 was found to bind not only to its consensus sites, but also to canonical AR binding sites (Zhao et al 2012). It is possible that the coordinate regulation of AR chromatin binding and transcriptional regulation by AKT, EZH2, and DNA methylation cause AR to drive cell proliferation and/or suppress genes associated with prostatic differentiation (Zhao et al 2012), thus contributing to the AR malignancy switch.…”

“…Using ChIP-seq, EZH2 was found to bind not only to its consensus sites, but also to canonical AR binding sites (Zhao et al 2012). It is possible that the coordinate regulation of AR chromatin binding and transcriptional regulation by AKT, EZH2, and DNA methylation cause AR to drive cell proliferation and/or suppress genes associated with prostatic differentiation (Zhao et al 2012), thus contributing to the AR malignancy switch.…”

Multifaceted role of EZH2 in breast and prostate tumorigenesis

“…A recent study by Zhao et al 115 highlights the previously overlooked role of AR as a global transcriptional repressor of several genes regulating cell differentiation and tumor suppression using a systems approach. The authors report that AR may play a dual role by inducing genes that promote prostatic differentiation while concomitantly repressing developmental regulators involved in non-prostatic pathways.…”

“…16 Recent reports suggest that EZH2 may promote prostate cancer progression by repressing tumor suppressor genes and developmental regulators and maintain a stem cell-like state by promoting a dedifferentiation program. 108,111,112 The molecular mechanism(s) reported to be responsible for the overexpression of EZH2 in prostate cancer include amplification of the EZH2 gene, 113 the deletion of its negative regulator miR-101114, transcriptional regulation by MYC 115 and ETS gene family members 129 as described in detail in Figure 2B. EZH2 and androgen signaling.…”

Targeting Enhancer of Zeste Homolog 2 as a promising strategy for cancer treatment

“…In B-cell Lymphoma cells, the pharmacological inhibition of EZH2 with DZNep in combination with JQ1 has a synergic effect in the suppression of cell growth and clonogenicity with a mechanism mediated by miR26a re-expression. The combined inhibition of Myc and EZH2 expression levels could result in an effective therapeutic strategy to successively suppress tumor growth in aggressive B-cell Lymphoma [124] .…”