Role of the Polycomb Repressive Complex 2 (PRC2) in Transcriptional Regulation and Cancer

Abstract

The chromatin environment is modulated by a machinery of chromatin modifiers, required for the specification and maintenance of cell fate. Many mutations in the machinery have been linked to the development and progression of cancer. In this review, we give a brief introduction to Polycomb group (PcG) proteins, their assembly into Polycomb repressive complexes (PRCs) and the normal physiological roles of these complexes with a focus on the PRC2. We review the many findings of mutations in the PRC2 coding genes, both loss-of-function and gain-of-function, associated with human cancers and discuss potential molecular mechanisms involved in the contribution of PRC2 mutations to cancer development and progression. Finally, we discuss some of the recent advances in developing and testing drugs targeting the PRC2 as well as emerging results from clinical trials using these drugs in the treatment of human cancers.

Figure 1.

PRC2 catalyzes H3K27 methylation. (A) The core PRC2 complex and substoichiometric interactors measured in HeLa cells (Smits et al. 2013). (B) Electron micrograph (EM) structure of a PRC2 complex with RBBP4 (RBAP48) and AEBP2 (EMDataBank 2236, deposited image) (Ciferri et al. 2012). (C) Graphic representation of time-dependent successive H3K27 methylation (Sneeringer et al. 2010). A longer residence time at CpG islands at promoters of untranscribed genes allows for establishment of a trimethylated domain. WT, Wild-type.

Figure 2.

Hyperactive EZH2 mutants in DLBCL and FL. (A) Histogram of EZH2 mutation frequencies in FL and DLBCL. These map to three residues in the catalytic SET domain. (B) The mutated residues (light blue) are found in the active catalytic site of EZH2 near substrate and cofactor (yellow). Y646 coordinates the substrate lysine’s side-chain amine and impedes rotation to allow transfer of the third methyl group, while A682 stabilizes the position of Y646. The crystal structure of the human EZH2 SET domain (PDB 4MI0) (Wu et al. 2013a) is used with substrate and cofactor from EHMT1 superimposed (PDB 2RFI) (Wu et al. 2010). (C) Combined activities of wild-type (WT) and Y646 mutant EZH2 achieves faster H3K27 trimethylation (Swalm et al. 2014).

Figure 3.

Loss-of-function PRC2 mutations in cancer. (A) Mutations conferring loss of PRC2 function are recurrent in several cancer types. The mutations are found in the genes coding for PRC2 core subunits or substoichiometric interaction partners, as well as in the genes coding for H3.1 and H3.3. (B) Histogram of EZH2 mutants found in T-cell acute lymphoblastic leukemia (T-ALL) and myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) (Ernst et al. 2010; Nikoloski et al. 2010; Abdel-Wahab et al. 2011; Bejar et al. 2011; Guglielmelli et al. 2011; Jankowska et al. 2011; Score et al. 2012; Muto et al. 2013; Lindsley et al. 2015). The missense mutations cluster in four hotspot regions. (C) Mutations in EED and SUZ12 found in malignant peripheral nerve sheath tumors (MPNSTs) (De Raedt et al. 2014; Lee et al. 2014; Zhang et al. 2014). (D) Crystal structure of Ezh2 and Suz12 VEFS domain from C. thermophilum (PDB 5CH1) (Jiao and Liu 2015) with Eed replaced by superimposed human EED (PDB3IIW) (Margueron et al. 2009). Right panel shows a schematic representation of the structure. (E) Loss-of-function mutations are frequently found in the part of EZH2 coding for the 50 amino acid pre-SANT region. In the structure D, the pre-SANT region (red) is sandwiched between EED (green) and the catalytic SET domain of Ezh2 (blue), and mutations likely affect SET domain function directly or perturb a putative allosteric communication between EED and Ezh2. (F) Loss-of-function mutations are frequently found in the part of EZH2 coding for the CXC domain. It has nine cysteines (light blue) that coordinate zinc ions in two separate clusters. All missense mutations (red) in this domain map to these clusters. Structure of the human CXC domain is used (PDB 4MI0) (Wu et al. 2013a). (G) The hotspot region for EZH2 mutations in the SET domain maps to the active site and surrounding binding pockets for substrate and cofactor. Structure used is of human SET domain (PDB 4MI0) with substrate and cofactor from EHMT1 superimposed (PDB 2RFI) (Wu et al. 2010). DIPG, Diffuse intrinsic pontine glioma.