Emerging Roles of LncRNAs in the EZH2-regulated Oncogenic Network

Abstract

Cancer is a life-threatening disease, but cancer therapies based on epigenetic mechanisms have made great progress. Enhancer of zeste homolog 2 (EZH2) is the key catalytic component of Polycomb repressive complex 2 (PRC2) that mediates the tri-methylation of lysine 27 on histone 3 (H3K27me3), a well-recognized marker of transcriptional repression. Mounting evidence indicates that EZH2 is elevated in various cancers and associates with poor prognosis. In addition, many studies revealed that EZH2 is also involved in transcriptional repression dependent or independent of PRC2. Meanwhile, long non-coding RNAs (lncRNAs) have been reported to regulate numerous and diverse signaling pathways in oncogenesis. In this review, we firstly discuss functional interactions between EZH2 and lncRNAs that determine PRC2-dependent and -independent roles of EZH2. Secondly, we summarize the lncRNAs regulating EZH2 expression at transcription, post-transcription and post-translation levels. Thirdly, we review several oncogenic pathways cooperatively regulated by lncRNAs and EZH2, including the Wnt/β-catenin and p53 pathways. In conclusion, lncRNAs play a key role in the EZH2-regulated oncogenic network with many fertile directions to be explored.

Keywords: EZH2; H3K27me3; PRC2; cancer; epigenetic regulation; lncRNA; non-histone methylation.

Figure 1

Models of lncRNA-mediated EZH2 action to regulate chromatin remodeling. (A) Schematic model of trans lncRNAs recruiting EZH2 to catalyze H3K27me3 and repress gene transcription. LncRNA (red curve, the same below) recruits PRC2 to the promoter of target genes, such as tumor suppressor genes, but inhibits the methyltransferase activity of EZH2, which can be relieved by JARID2 binding. (B) Characteristics of interaction between EZH2 and lncRNAs. EZH2, EED and SUZ12 are the core subunits of PRC2. Phosphorylation of EZH2 at T350 mediated by CDK1/2 is essential for its association with lncRNAs, and preferentially binds to G-quadruplex RNA. (C) Regulation of PRC2 activity by cis-acting RNAs. PRC2 scans nascent RNAs and then binds to G-tract regions. With slow transcription, EZH2 binding to nascent RNAs can promote H3K27me3 on chromatin to repress gene expression; with fast transcription, pre-existing PRC2 can bind nascent RNAs and then be evicted from the promoter, leading to gene activation.

Figure 2

LncRNAs involved in regulation of EZH2 expression and activity. (A) The PRC2- or EZH2-associated lncRNAs regulate the expression of various genes, including lncRNAs. Many lncRNAs inhibit EZH2 methyltransferase activity, which can be relieved by JARID2 binding leading to reduced PRC2-RNA interaction and subsequently enhanced EZH2 activity. (B) EZH2 directly methylates non-histone proteins independent on PRC2: LincRNA-p21 disrupts PRC2 through competitively binding EZH2, and enhances the EZH2-pS21 by AKT, resulting in the coactivation of methylated STAT3. (C) Lnc-β-Catm stabilizes β-catenin protein through directly promoting its methylation by EZH2. (D) At the transcriptional level: LncRNAs, such as NR-104098 and GAS5, suppress EZH2 transcription through recruiting transcription factors, such as E2F1 and E2F4, respectively. (E) At the post-transcriptional level: ceRNAs scavenge microRNAs, and thus prevent the EZH2 mRNA from degradation and translational inhibition. (F), (G) and (H) At the post-translational level: lncRNAs, such as ANCR, directly bind EZH2 and enhance pT350 through increasing its interaction with CDK1, leading to EZH2 ubiquitination and proteasomal degradation (F). FAM83C-AS1 recruits deubiquitinase ZRANB1 to stabilize EZH2 (G). PVT1 improves EZH2 stability through blocking EZH2-pT350 to antagonize its ubiquitination, and EZH2 can also stabilize MDM2 through direct interaction. PVT1 also recruits EZH2 to repress gene transcription (H).