Polycomb- and Methylation-Independent Roles of EZH2 as a Transcription Activator

Abstract

SUMMARY Enhancer of Zeste 2 (EZH2) is the enzymatic subunit of Polycomb Repressive Complex 2 (PRC2), which catalyzes histone H3 lysine 27 trimethylation (H3K27me3) at target promoters for gene silencing. Here, we report that EZH2 activates androgen receptor (AR) gene transcription through direct occupancy at its promoter. Importantly, this activating role of EZH2 is independent of PRC2 and its methyltransferase activities. Genome-wide assays revealed extensive EZH2 occupancy at promoters marked by either H3K27ac or H3K27me3, leading to gene activation or repression, respectively. Last, we demonstrate enhanced efficacy of enzymatic EZH2 inhibitors when used in combination with AR antagonists in blocking the dual roles of EZH2 and suppressing prostate cancer progression in vitro and in vivo. Taken together, our study reports EZH2 as a transcriptional activator, a key target of which is AR, and suggests a drug-combinatory approach to treat advanced prostate cancer.

Androgen receptor enhancer usage and the chromatin regulatory landscape in human prostate cancers

“…ChIP-seq experiments in cell lines revealed substantial co-occupancy of ERG and AR chromatin binding, together with transcriptional corepressors enhancer of zeste homolog 2 (EZH2) and histone deacetylases (HDACs) attenuating AR target gene expression (Kunderfranco et al 2010, Yu et al 2010, Chng et al 2012. However, EZH2 has recently also been reported to activate AR signaling, which is distinct from its conventional role in epigenetic silencing (Kim et al 2018). The non-polycomb repressive complex 2 (PRC2) function of EZH2 is consistent with previous work, which reported enriched AR motifs at EZH2-binding sites depleted of the repressive histone mark H3K27me3 (Xu et al 2012).…”

Catalytic inhibition of KDM1A in Ewing sarcoma is insufficient as a therapeutic strategy

“…These characteristics coincide with other epigenetic regulators such as EZH2. Its emerging methyltransferase‐ and polycomb‐independent roles provide novel therapeutic potential for inhibitors disrupting its docking capacity …”

“…Its emerging methyltransferase-and polycomb-independent roles provide novel therapeutic potential for inhibitors disrupting its docking capacity. 39 In line with this model, recent reports in prostate cancer cell lines described a scaffolding role for KDM1A, whereby catalytically inactive KDM1A was still able to establish the prostate cancer gene network and ensure survival of castration-resistant prostate cancer cell lines. 40 This was further confirmed with the tool compound SP2509, proposed as an allosteric inhibitor binding to the H3 pocket region of KDM1A, capable of inducing cell death in prostate cancer cell lines.…”

Chromatin reprogramming as an adaptation mechanism in advanced prostate cancer

“…Earlier data supported the notion that EZH2 overexpression drives emergence of CRPC in a PRC2-independent manner, thus independently of its histone methyltransferase activity (Xu et al 2012). Recently, using a ChIP-seq approach, EZH2 was shown to occupy the AR promoter and act as a transcriptional activator for AR transcription (Kim et al 2018), suggesting that its overexpression in t-NEPCs compared to CRPC adenocarcinomas (Clermont et al 2015) may actually be associated also with its increased coactivator-function rather than its function in deposition of the repressive H3K27me3 mark. Clermont et al showed that several histone-modifying enzymes with chromatin remodeling activity, including CBX2 and EZH2, were upregulated in t-NEPCs as compared to CRPC adenocarcinomas (Clermont et al 2015).…”