Polycomb and Trithorax Group Proteins: The Long Road from Mutations in Drosophila to Use in Medicine

Abstract

Polycomb group (PcG) and Trithorax group (TrxG) proteins are evolutionarily conserved factors responsible for the repression and activation of the transcription of multiple genes in Drosophila and mammals. Disruption of the PcG/TrxG expression is associated with many pathological conditions, including cancer, which makes them suitable targets for diagnosis and therapy in medicine. In this review, we focus on the major PcG and TrxG complexes, the mechanisms of PcG/TrxG action, and their recruitment to chromatin. We discuss the alterations associated with the dysfunction of a number of factors of these groups in oncology and the current strategies used to develop drugs based on small-molecule inhibitors.

Keywords: Drosophila; EZH2 inhibitors; PRC2; PRC2 inhibitors; PRE; Polycomb; Trithorax; cancer, oncology; small-molecule inhibitors.

Fig. 1

Main Polycomb group complexes. (A) PRC2 complexes. Drosophila subunits are shown on the left, and their mammalian orthologs are presented on the right-hand side of the figure. In Drosophila and mammals, the PRC2 core is composed of E(z)–Su(z)12–Esc–Caf1 and EZH2–SUZ12–EED–RBBP7/4, respectively. Drosophila Esc and mammalian EZH2 can be replaced by their homologs Escl and EZH1, respectively. The PRC2.1 complex contains either Pcl or PCL1/2/3 in Drosophila and humans, respectively; The PRC2.2 complex contains either Jarid2/Jing or JARID2/ AEBP2 in Drosophila and humans, respectively. (B) PRC1 complexes. The PRC1 core is composed of the Sce–Psc and RING–PCGF heterodimers in Drosophila and mammals, respectively. In cPRC1, the core subunits associate with Pc–Ph in Drosophila and their orthologs CBX–PHC in humans. In ncPRC1, the core subunits associate with Kdm2 in Drosophila and with the RYBP (or YAF2) subunit in humans. In humans, the cPRC1 and ncPRC1 complexes can be further distinguished by the presence of a specific PCGF subunit (cPRC1.2, cPRC1.4, ncPRC1.1, ncPRC1.3, ncPRC1.5, and ncPRC1.6 subcomplexes); other specific subcomplex subunits are indicated next to the complex name. (C) The PR–DUB complex. PR–DUB is composed of Asx–Calypso and ASXL1/2–BAP1 in Drosophila and humans, respectively. The size of the ovals representing the proteins corresponds to the relative size of the protein molecules

Fig. 2

Main Trithorax group complexes. (A) The BAP and PBAP complexes of the SWI/SNF subfamily. The subunits common to both complexes are colored in red; specific BAP and PBAP subunits are shown in pink. Human subunits whose presence in Drosophila BAP/ PBAP complexes has not been confirmed are depicted in grey. (B) COMPASS and COMPASS-like complexes. The subunits common to the three complexes are colored in orange; the specific subunits are presented in yellow. (C) Drosophila TAC1 complex (not confirmed as present in humans). The size of the ovals representing proteins corresponds to the relative size of the protein molecules

Fig. 3

Functional activities of the Polycomb/Trithorax group proteins. The PRC1 complex compacts chromatin, mediates nucleosome ubiquitination (H2AK118Ub in Drosophila, H2AK119Ub in mammals), and also specifically binds to the nucleosome tri-methylated at H3K27. The PRC2 complex is responsible for the H3K27me3 histone modification; it interacts with the H2AK118/9Ub nucleosomes. The PR-DUB complex deubiquitinates H2AK118/9Ub nucleosomes. Trithorax group activator complexes decompact chromatin (SWI/SNF), acetylate histones (TAC1), and catalyze H3K4 methylation (COMPASS). DNA-binding factors (DNA-BF) and hypomethylated CpG islands (CGIs) are involved in the recruitment of the PcG/TrxG complexes to chromatin

Fig. 4

Disruption of the PRC2 core subunits’ activity in carcinogenesis. The “+” sign against the pink background stands for cases of hyperactivation of the PRC2 enzyme (overexpression or GOF mutations); “+”against the blue background stands for cancer associated with a loss of the PRC2 function (LOF mutations); “PP” (Poor Prognosis) indicates that the PRC2 subunit dysfunction was shown to correlate with a poor survival prognosis. MDS/MPN – myelodysplastic/myeloproliferative neoplasm

Fig. 5

Schematic representation of the mechanisms of suppression of PRC2 hyperactivity by small-molecule inhibitors. EPZ005687, GSK126, EI1, and EPZ6438 (tazemetostat) target the EZH2 SET domain and inhibit the transfer of a methyl group from S-adenosylmethionine (SAM) to histone H3 lysine 27 (H3K27). UNC1999, OR-S1, and OR-S2 suppress the activity of EZH2 and its close homolog, EZH1. SAH-EZH2 inhibits the interaction between EZH2 and EED, which leads to destabilization of the PRC2 complex. A-395 and EED226 suppress the recruitment of the EED protein to the H3K27me3 modification, eliminating the stimulation of the PRC2 methyltransferase activity. MS1943 recognizes the unique three-dimensional structure of the EZH2 protein and directs it to the proteasome degradation pathway