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Enhancer of Zeste Homolog 2 Histone Modification
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This entry is adapted from the peer-reviewed paper 10.3390/cancers15020425

Enhancer of zeste homolog 2 (EZH2) is the catalytic subunit of the polycomb repressor complex 2 (PRC2), which trimethylates histone 3 at Lys-27 and regulates the expression of downstream target genes through epigenetic mechanisms.

enhancer of zeste homolog 2 H3K27 epigenetics

1. Introduction

Gastric cancer (GC) is the fifth most diagnosed malignancy worldwide, with more than 1 million new cases annually [1]. There is a lack of methods to diagnose GC early, so many patients are diagnosed at a later stage, which leads to a high mortality rate for GC patients [1]. It was reported that more than 784,000 GC patients died worldwide in 2018, making it the third most common cause of death among oncologic diseases [2]. The complicated pathogenesis, late diagnosis and lack of effective treatment for GC lead to the poor prognosis of patients. To fundamentally prevent and treat GC, it is highly significant to understand the pathogenesis of GC [3]. In addition to genetic changes and environmental factors, it has been proven that epigenetic inheritance guides the occurrence and development of cancer and is a hallmark of gastric malignancies [4]. It was known that the polycomb group (PcG) was one of the most important epigenetic regulators, which influences the expression of many genes involved in the development of the body [5]. As a core member of the PcG family, EZH2 plays a vital role in cell proliferation, differentiation and tumor formation through H3K27me3-mediated downstream gene silencing. The expression of H3K27me3 in GC tissues is significantly increased, and it is the most common type of histone methylation modification in GC studies, which is closely related to the pathogenesis of GC and the prognosis of patients [4][6]. In conclusion, EZH2 plays a role in the pathogenesis of GC through H3K27me3. For these reasons, EZH2 can be considered an exciting target for developing targeted therapies for GC. 

2. Overview of EZH2

PcG proteins are a group of transcriptional repressors that regulate target genes through chromatin modification and can induce tumor development. These proteins chemically and functionally represent the core proteins of the polycomb repressive complexes (PRCs) [5]. PRCs are enzyme complexes that modify lysine residues on histones [7][8]. There are two major PRCs in mammals: Polycomb repressive complex 1 (PCR1) and polycomb repressive complex 2 (PCR2). PRC1 consists of ring finger protein 1 (RING 1) (RING1A or RING1B) and PcG ring finger protein (PCGF1-6) that monoubiquitinates lysine 119 on histone H2A (H2AK119ub1) [9]. PRC2 complexes are histone methyltransferases (HMTases) that are dependent on S-adenosyl-L-methionine (SAM) and contain four major core subunits: EZH2/1, suppressor of zeste 12 (SUZ12), embryonic ectoderm development 1-4 (EED1-4) and RBAP46/48 [9][10]. It catalyzes the mono-methylation, di-methylation and tri-methylation of lysine 27 on histone H3 (H3K27me1, H3K27me2 and H3K27me3 [11]. PRC2 is further divided into two different subclasses: PRC2.1 and PRC2.2. In addition to the four major core structures, the former includes Jumonji AT-rich interactive domain 2 (JARID2) and adipocyte enhancer binding protein 2 (AEBP2), the latter of which includes PCL1-3 and c17orf96/c10orf12 [11] (Figure 1). At present, the accessory proteins have been shown to regulate PRC2 activity and play a role in cells by localizing PRC2 to chromatin. However, the exact function of these proteins is unknown.

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Figure 1. The core structure of PRCs, including PRC1 and PRC2. PRC1 complexes are E3 ubiquitin ligases that monoubiquitinate lysine 119 of histone H2A (H2AK119ub1), consisting mainly of two core subunits. PRC2 consists of four major core subunits and binds to different non-core subunits divided into PRC2.1 and PRC2.2. PRC2 catalyzes the monomethylation, dimethylation, and trimethylation of lysine 27 on histone H3 (H3K27me1, H3K27me2, and H3K27me3). SAM provides the methyl group for the reaction catalyzed by histone methyltransferase.
EZH2 is a critical functional member of the PRCs family, which is located in chromosome 7q35 and consists of 20 exons containing 746 amino acid residues [12] (Figure 2C). It has five structural domains, including the EED-interacting structural domain (EID), structural domain I, structural domain II (SANT2L), a cysteine-rich structural domain (CXC structural domain), and a three-chested structural domain (SET structural domain) [12][13] (Figure 2D). Its most critical function is to inhibit gene expression by promoting histone methylation and DNA methylation in the nucleus.
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Figure 2. The gene and protein structure of the EZH2. (A) The location of the EZH2 protein in the cell. (B) The chromosome localization of EZH2. (C) The protein secondary structure of EZH2. (D) Schematic representation of the organization of the five functional domains in EZH2 is depicted. The EID structural domain is the binding site for the EED subunit in the RC2 complex. The domain II structural domain is the linkage site for the SUZ12 subunit in the PRC2 complex. The SET structural domain is the site that exerts methyl transfer activity and is also the binding site for SAM. The CXC structural domain also contributes to methyl transfer activity, whereas the function of the domain I structural domain is not known.

3. Histone Modificaton of EZH2

Histones are an essential part of the nucleosome, the basic structure of chromosomes. The modification of histones can change the loose or agglutination state of chromatin which has a regulatory effect on gene expression similar to that of the DNA genetic code [14]. It was clarified that H3K27me3 is considered a key epigenetic event that can make the chromosome structure denser to inhibit the expression of target genes [15]. EZH2, a histone methyltransferase in the human genome, catalyzes the lysine trimethylation of histone 3 at position 27 (H3K27me3), which leads to the silencing of its target genes involved in cell proliferation, cell differentiation, and cancer development [16][17]. However, it is noteworthy that EZH2 alone cannot exert its methyltransferase biological activity. EZH2 must be combined with at least two non-catalytic partners, SUZ12 and EED, to obtain a strong histone methyltransferase activity [18][19][20]. In addition, EZH2 typically forms PRC2 complexes to perform histone-modifying processes, which is the classical mode of action of EZH2 and will be explicitly described below. EZH2 is overactive in cancer cells through functionally acquired mutations and overexpression. In a study on prostate cancer, elevated levels of EZH2 and H3K27me3 were associated with poor prognosis in metastatic prostate cancer. However, the deletion of EZH2 inhibited the growth of prostate cancer cells [21]. The overexpression of EZH2 and elevation of H3K27me3 in solid cancers, including breast, gastric, endometrial, ovarian, melanoma, bladder, kidney, colorectal, and lung cancers, as well as hematological malignancies such as T-cell and B-cell lymphomas [22][23]. In conclusion, the histone modification of EZH2 is closely related to tumorigenesis. The overexpression of EZH2 leads to an increase in H3K27me3, which inhibits tumor suppressor genes including p16 and E-cadherin, and drives cellular differentiation [24] (Table 1).
Table 1. The genes that are regulated by EZH2 through histone modifications.
Table
Genes Mechanism of Action of EZH2 The Role of Genes Reference
METTL3 EZH2 overexpression leads to increases in H3K27me3, up-regulating the expression of METTL3 Drug resistance [25]
P16 EZH2 overexpression leads to increases in H3K27me3, inhibiting the expression of P16 Inhibition of tumor growth;
Drive cellular differentiation		 [26]
E-cadherin EZH2 overexpression leads to increases in H3K27me3, inhibiting E-cadherin Inhibition of tumor growth [26]
HIF-1α EZH2 stabilizes the expression of HIF-1α Promotion of tumor growth and metabolism favoring glycolysis [5]
INK4B-ARF-INK4A EZH2 suppresses the expression of INK4B–ARF–INK4A Induce cell cycle progression and inhibit cell senescence [27]
Note: METTL3: methyltransferase-like 3; HIF-1α: hypoxia inducible factor-1.

References

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  17. Viré, E.; Brenner, C.; Deplus, R.; Blanchon, L.; Fraga, M.; Didelot, C.; Morey, L.; Van Eynde, A.; Bernard, D.; Vanderwinden, J.M.; et al. The Polycomb group protein EZH2 directly controls DNA methylation. Nature 2006, 439, 871–874.
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  23. Hanaki, S.; Shimada, M. Targeting EZH2 as cancer therapy. J. Biochem. 2021, 170, 1–4.
  24. Bracken, A.P.; Kleine-Kohlbrecher, D.; Dietrich, N.; Pasini, D.; Gargiulo, G.; Beekman, C.; Theilgaard-Mönch, K.; Minucci, S.; Porse, B.T.; Marine, J.C.; et al. The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells. Genes Dev. 2007, 21, 525–530.
  25. Li, F.; Chen, S.; Yu, J.; Gao, Z.; Sun, Z.; Yi, Y.; Long, T.; Zhang, C.; Li, Y.; Pan, Y.; et al. Interplay of m(6) A and histone modifications contributes to temozolomide resistance in glioblastoma. Clin. Transl. Med. 2021, 11, e553.
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Subjects: Oncology
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wuhan yu
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ning Liu
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Update Date: 31 Jan 2023
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