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. 2021 Feb 24;112(4):1376–1382. doi: 10.1111/cas.14840

The noncanonical role of EZH2 in cancer

Jinhua Huang 1, Hongwei Gou 1, Jia Yao 1, Kaining Yi 1, Zhigang Jin 1, Masao Matsuoka 2,3, Tiejun Zhao 1,3,✉
PMCID: PMC8019201  PMID: 33615636

Abstract

Enhancer of zeste homolog 2 (EZH2) is the catalytic subunit of polycomb repressive complex 2 (PRC2). Dysregulation of EZH2 causes alteration of gene expression and functions, thereby promoting cancer development. The regulatory function of EZH2 varies across different tumor types. The canonical role of EZH2 is gene silencing through catalyzing the trimethylation of lysine 27 of histone H3 (H3K27me3) in a PRC2‐dependent manner. Accumulating evidence indicates that EZH2 has an H3K27me3‐independent function as a transcriptional coactivator and plays a critical role in cancer initiation, development, and progression. In this review, we summarize the regulation and function of EZH2 and focus on the current understanding of the noncanonical role of EZH2 in cancer.

Keywords: cancer, carcinogenesis, EZH2, H3K27me3, PRC2

In this review, we summarize the regulation and function of EZH2 and focus on the current understanding of the noncanonical role of EZH2 in cancer.

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1. INTRODUCTION

The polycomb group (PcG) proteins were first identified in Drosophila as regulatory factors that transcriptionally silence the expression of the bithorax homeobox (Hox) gene cluster. 1 It has been reported that PcG proteins interact with each other and generate two major complexes, polycomb repressive complexes 1 and 2 (PRC1 and PRC2). 2 PcG complexes play a synergistic role in the transcriptional suppression of target genes through methylation of lysine residues in the histone tails. PRC2 is a highly conserved complex in many species of plants and animals. It is mainly composed of four subunits: EZH2, EED, SUZ12, and RbAp46/48 (Figure 1A). 3 Enhancer of zeste homolog 2 (EZH2), the core catalytic subunit of the PRC2 complex, plays a critical role in regulating a wide range of biological processes, including tumor development and malignancy, stem cell renewal and development, immune response, and cell senescence. 4 Numerous studies have discovered that EZH2 functions together with EED and SUZ12 and induces gene silencing mainly through trimethylation of histone H3 lysine 27 (H3K27me3). 5 , 6 , 7 Recently, additional findings supporting a PRC2‐independent role for EZH2 have emerged. 8 , 9

FIGURE 1.

FIGURE 1

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The polycomb repressive complex 2 (PRC2) complex composition, regulation function, and schematic diagram of the enhancer of zeste homolog 2 (EZH2) domains. A, The PRC2 complex contains four core subunits which include EZH2, EED, SUZ12, and RbAp46/48. PRC2 induces target genes’ transcriptional repression through EZH2‐mediated H3K27 trimethylation. B, EZH2 has four domains: WD‐binding domain; PRC2 HTH 1 domain, CXC domain, and SET domain

2. EZH2 AND ITS EXPRESSION IN CANCER

Human EZH2 gene is located on the long arm of chromosome 7 at 7q35. It contains 20 exons and encodes a protein composed of 746 amino acids. 10 Sequence analysis revealed that EZH family proteins contain four homologous domains, including homologous domain I (H1 domain), homologous domain II (H2 domain), cysteine‐rich domain, and C‐terminal SET domain. 11 EZH2 is the core catalytic subunit of PRC2, and its SET domain at the C‐terminus provides the histone methyltransferase activity (Figure 1B). When the PRC2 complex is formed and recruited to the promoter region of the target genes, the SET domain of EZH2 catalyzes H3K27me3, leading to silencing its target genes involved in cell proliferation, cell differentiation, and cancer development. 12

A series of studies have shown that overexpression and mutation of EZH2 were observed in many human cancers, including breast cancer, prostate cancer, endometrial cancer, melanoma, bladder cancer, colon cancer, liver cancer, lung cancer, lymphoma, etc. (Table 1). 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 Overexpression of EZH2 can lead to disruptions in cell proliferation, apoptosis, migration, and invasion. High level of EZH2 is also correlated with poor prognosis in cancers. 13 , 14 In addition, activating or inactivating mutations of EZH2 have been identified in a variety of cancers (Table 1). 21 , 22 , 23 , 24 , 25 Point mutations at tyrosine 641 in the catalytic SET domain of EZH2 occur in diffuse large B‐cell lymphomas and follicular lymphomas. Y641 mutation is proved to be a gain‐of‐function mutation of EZH2, which leads to the increase of the transformation from H3K27 to trimethylated form. 21 , 22 Inactivating mutations of EZH2, such as deletion, nonsense and missense mutations, and frameshift, emerge in myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN), and human T‐cell acute lymphoblastic leukemia (T‐ALL). It results in the loss‐of‐function of EZH2, and such mutated EZH2 functions as a tumor suppressor in cancer. 24 , 25

TABLE 1.

EZH2 overexpression and mutations in different cancer types

Status Associated cancer type Reference
Overexpression Breast, prostate, endometrial, melanoma, bladder, colon, liver, lung, and lymphoma 13, 14, 15, 16, 17, 18, 19, 20
Activating mutations Diffuse large B‐cell lymphoma and follicular lymphoma 21, 22
Inactivating mutations MDS, MPN, T‐ALL 24, 25
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Abbreviations: MDS, myelodysplastic syndrome; MPN, myeloproliferative neoplasms; T‐cell acute lymphoblastic leukemia, T‐ALL.

3. METHYLASE‐DEPENDENT FUNCTIONS OF EZH2 IN CANCER

EZH2 plays a vital role in epigenetic gene silencing, which usually depends on its histone methyltransferase activity. Numerous studies showed that EZH2 functions as the catalytic subunit of the PRC2 complex to catalyze H3K27me3. Then the PRC binds to H3K27me3 and lysine 119 of monoubiquitinated histone H2 (H2AK119‐ub1) to form a ternary complex. The complex acts as a transcriptional inhibitor to mediate chromatin compaction, resulting in the silencing of its downstream target genes. 26

The canonical role of EZH2 is mainly to silence multiple tumor suppressor genes through its histone lysine methyltransferase activity (Figure 2A). The EZH2 target genes involved in cell proliferation, cell apoptosis, and cell cycle regulation include INK4B‐ARF‐INK4A, Bim, TRAIL, KLF2, MSMB, FOXC1, hDAB2IP, etc. 20 In addition, EZH2 harboring an activation point mutation at residue Y641, A677, or A687 has enhanced methyltransferase activity, which results in the increase of H3K27me3 levels (Figure 2B). 21 , 22 , 27 , 28 EZH2 point mutations at residues A677 and A687 were found in non‐Hodgkin's lymphoma (NHL), leading to hypertrimethylation of H3K27. The long noncoding RNAs (lncRNAs) also participate in the EZH2‐mediated epigenetic regulation. Luo et al found that upregulated lncRNA H19 enhanced the metastasis of bladder cancer by binding to EZH2, and the EZH2/H19 complex subsequently inhibited the expression of E‐cadherin by H3K27me3 (Figure 2C). 29

FIGURE 2.

FIGURE 2

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Schematic representation of the methylase‐dependent functions of enhancer of zeste homolog 2 (EZH2). A, EZH2 catalyzes lysine 27 of histone H3 trimethylation (H3K27me3) and silences its target genes. B, EZH2 with gain‐of‐function mutations at residues Y641, A677, or A687 results in the increase of H3K27me3 levels. C, EZH2 can be recruited by long noncoding RNA (lncRNA) to its target genes and increases H3K27me3 levels via EZH2–lncRNA interaction. D, Histone deacetylase (HDAC) deacetylates H3K27 by cooperating with EZH2 so that the ε‐amino group can be methylated by EZH2. E, EZH2 recruits DNA methyltransferase (DNMT), which methylates H3K27 of CpG DNA, leading to the silencing of related target genes

A series of studies have shown that EZH2 may cooperate with other epigenetic regulators, such as DNA methyltransferases (DNMTs) and histone deacetylases (HDACs), to fulfill its epigenetic silencing function. 30 , 31 , 32 Studies reported that HDAC deacetylate the lysine at H3K27 or H3K29, H3K14, and H4K8, and the ε‐amino group of the lysine side chain is involved in the methylation process of EZH2 (Figure 2D). 33 In addition, the EZH2 could directly interact and cooperate with DNMT to control CpG methylation and silence gene transcription (Figure 2E). 32 During cellular transformation, EZH2 participated in the CpG‐hypermethylation modification of certain genes, thereby inducing tumorigenesis. 33

4. PRC2‐INDEPENDENT ROLES OF EZH2 IN CANCER

4.1. EZH2 act as transcriptional activator/coactivator

Accumulating evidence shows that the function of EZH2 is independent of its role as a PRC2‐associated repressor, and it acts as a transcriptional coactivator in various tumors (Figure 3A). 34 , 35 In endocrine‐related cancer such as breast cancer, EZH2 could activate gene transcription and promote the proliferation of tumor cells independently of its methyltransferase activity. 35 , 36 , 37 However, the molecular mechanisms differ depending on the type of cancer. In the ER+ breast cancer cell line MCF‐7, domain I (amino acid 1‐159) of EZH2 directly interacts with estrogen receptor alpha (ERα) and β‐catenin to form a ternary complex. EZH2 exerts its transactivation activity to activate the promoter of c‐Myc and cyclin D1 through recruiting the EZH2/ERα/β‐catenin complex to its TCF/β‐catenin–binding sites. 35 EZH2 could also enhance the transcription of c‐Myc and cyclin D1 via recruitment of EZH2 to the T‐cell–specific transcription factor (TCF)/lymphoid enhancer‐binding factor (LEF) binding sites in the c‐Myc and cyclin D1 promoters, and this transcriptional activation is independent of H3K27me3. 36 In addition, EZH2 interacts with Trim28 and chromatin remodeling protein SWI/SNF and activates the expression of CXCR4 in a PRC2‐independent way, resulting in promotion of mammary stem cell enrichment and maintenance. 38 In ER‐negative basal‐like breast cancer cells, EZH2 forms a ternary complex with NF‐κB subunit RelA and RelB, and activates the transcription of NF‐κB target genes such as IL6 and TNF through recruiting the EZH2/RelA/RelB complex to their promoters. 34 Moreover, in chronic lymphocytic leukemia (CLL) cases, EZH2 recruits MYC protein and binds to the IGF1R promoter to activate the transcription of IGF1R gene in a PRC2‐independent manner, leading to the activation of its downstream PI3K/AKT signaling. 39 In adrenocortical carcinoma (ACC), EZH2 cooperates with transcription factor E2F1 to upregulate the expression of aggression‐related genes, such as RRM2, PTTG1, and ASE1/PRC1, in a histone methyltransferase–independent manner, thereby promoting the development of ACC. 40 Avni et al reported that polycomb proteins, such as YY1, Mel‐18, Ring1A, EZH2, and EED, are recruited to the promoter of interleukin‐4 (IL‐4) and interferon‐γ (IFN‐γ), and induce the transcription of IL‐4 and IFN‐γ cytokines in differentiated T helper cells. 41 It has been reported that EZH2 can activate oncogenic signaling pathways through its binding proteins. PCNA‐associated factor (PAF) is overexpressed in colon cancer, and it promotes the proliferation of cancer cells by activating the Wnt signaling pathway. Jung et al 42 identified a protein complex composed of PAF, EZH2, and β‐catenin in colon cancer cells. When the Wnt pathway is activated, PAF dissociates from PCNA and binds to β‐catenin. Then, it recruits EZH2 to form a ternary complex, leading to the binding and activation of the Wnt signaling. In addition, the highly activated hypoxia‐inducible factor 1‐α (HIF1‐α) in triple‐negative breast cancer cells (TNBCs) could inhibit PRC2. It led to the formation of a complex of EZH2 and forkhead box M1 (FoxM1), and occupied the promoter of matrix metalloproteinase gene (MMPs). Finally, EZH2/FoxM1 coactivates the expression of MMPs and promotes the invasion of TNBCs, independently of PRC2. 43

FIGURE 3.

FIGURE 3

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The molecular mechanisms of the role of enhancer of zeste homolog 2 (EZH2) in a polycomb repressive complex 2 (PRC2)‐independent manner. A, EZH2 acts as a transcriptional coactivator by forming complexes with other transcription factors. B, EZH2 acts as a transcription factor via directly binding to the target genes’ promoter. C, The phosphorylation of EZH2 turns it from a chromatin silencer to a transcriptional coactivator. D, EZH2 can methylate or phosphorylate nonhistone substrates to regulate gene silencing and transactivation in a PRC2‐dependent or ‐independent manner. E, EZH2 binds to internal ribosome entry site 1 (IRES1) of p53 mRNA to promote the expression of p53 protein. F, EZH2 forms a complex with long noncoding RNA (lncRNA) ANRIL and p65 to activate the NF‐κB pathway

In addition to its role as a transcriptional coactivator through forming a complex with other proteins, EZH2 also acts as a transcription factor via directly binding to the target genes’ promoter (Figure 3B). Lawrence et al found that EZH2 could bind to the promoter of RelB as a transcriptional activator in TNBCs and activated RelB transcription, thereby maintaining the self‐renewal of breast cancer tumor‐initiating cells (TNBC‐TICs). 44 Moreover, Kim et al reported that EZH2 directly binds to the promoter of androgen receptor (AR) gene. It induces the transcription of AR and its downstream target genes, such as PSA, TMPRSS2, and FKBP5, in a PRC2‐independent manner, which results in the development of prostate cancer. 45 Natural killer/T‐cell lymphoma (NKTL) is a highly aggressive malignancy of NK cells. 46 EZH2 promotes proliferation of NKTL cells by enhancing the transcription of Cyclin D1 gene, which is independent of its histone methyltransferase activity. Meanwhile, the EZH2 mutant deficient for histone methyltransferase activity is still able to promote cell growth. 19

A series of studies have demonstrated that biochemical modification of EZH2 induced the dissociation from the PRC2 complex and converted EZH2 from a transcriptional repressor into a transcription activator in a PRC2‐independent manner (Figure 3C). Yan et al found that JAK3 phosphorylated EZH2 in NKTL and then induced the release of EZH2 from the PRC2 complex, resulting in the downregulation of the global H3K27me3 levels in lymphoma cells. The free EZH2 soon formed a complex with pol II and activated the expression of genes related to DNA replication, cell cycle regulation, and tumor cell invasion, leading to the development of NKTL. 47 Meanwhile, the threonine residues at position 367 of EZH2 could be phosphorylated by p38α in invasive ER‐breast cancer cells and led to the cytoplasmic localization of EZH2. Cytoplasmic pEZH2 (T367) potentiated a PRC2‐independent interaction with cytoskeletal regulatory proteins and promoted breast cancer metastasis. 48 In castration‐resistant prostate cancer (CRPC), EZH2 acts as a transcriptional activator to induce carcinogenesis. Xu et al reported that Ser21 of EZH2 was phosphorylated by AKT1. After phosphorylation, EZH2 formed a complex with AR and exerted its oncogenic functions in prostate cancer, independently of its polycomb repressive activity. 49

4.2. Modification of nonhistone substrates by EZH2

EZH2 can also methylate or phosphorylate nonhistone substrates to regulate multiple cellular activities in a PRC2‐dependent or ‐independent manner (Figure 3D). It has been reported that EZH2 directly methylated transcription factors such as GATA4 and RORα. 50 , 51 However, the underlying mechanism and function were unknown. Ji Min Lee et al screened the proteins which have a similar sequence to the domain methylated in histone H3K27 and named the amino acid sequence "R‐K‐S". Studies showed that EZH2 could induce the methylation of lysine in the R‐K‐S sequence of the RORα transcription factor. Subsequently, methylated RORα was recognized by the DDB1/DCAF1/CUL4 ubiquitin ligase complex, leading to ubiquitination and degradation of the tumor suppressor protein RORα. 51 Zheng et al found that overexpression of EZH2 in oral squamous cell carcinoma (OSCC) patients enhances cell migration and invasion, as well as glycolysis‐mediated epithelial‐mesenchymal transition (EMT). Further studies indicated that ectopic overexpression of EZH2 elevated the phosphorylation of STAT3 at the 705 residue, downregulated FoxO1 expression, and thereby promoted tumor growth and glycolysis of OSCC. 52 Similarly, AKT1‐mediated phosphorylation of EZH2 at Ser21 in glioblastoma allows EZH2 to bind and induce methylation of STAT3 at K180 in a PRC2‐independent manner. It thus enhances the activity of STAT3 by increasing phosphorylation of STAT3 at Y705 in glioma stem cells (GSCs), thereby promoting gene transcription and clonogenic growth of GSCs. 53 In addition, PLZF is an important transcription factor which regulates the function of NKT cells. EZH2 directly induces the methylation of PLZF protein, which leads to its ubiquitination and degradation. It is thus indicated that EZH2 may be involved in controlling the development of NKT cells and maintaining immune homeostasis. 54

4.3. EZH2 acts as RNA‐binding protein

EZH2 has been shown to interact with lncRNAs or mRNAs to promote the expression of oncogenes. A recent study indicated that EZH2 directly bound to the internal ribosome entry site 1 (IRES1) of p53 mRNA 5’UTR (Figure 3E). It finally enhanced the stability of p53 mRNA and promoted the translation of p53 protein. In addition, EZH2 elevated the expression of p53 GOF mutant protein in a histone methyltransferase–independent manner, leading to the growth and metastasis of cancer cells. 55 We previously reported that the expression of lncRNA ANRIL was significantly enhanced in HTLV‐1–infected cell lines and clinical adult T‐cell leukemia (ATL) samples. Knockdown of ANRIL inhibited the proliferation of ATL cells and induced cell apoptosis. A further study revealed that ANRIL associated with EZH2 and p65 protein to form a ternary complex, which finally resulted in the activation of the NF‐κB signaling pathway in an EZH2 methyltransferase–independent manner (Figure 3F). 56

4.4. Regulatory function of EZH2 at other cellular levels

In addition to the regulation at transcriptional level, EZH2 also functions in other manners. A recent study has shown that EZH2 has a noncatalytic function in overcoming cisplatin resistance in small cell lung cancer (SCLC) by promoting nucleotide excision repair (NER). Further experiments demonstrated that EZH2 interacted with DDB1‐DDB2 and stabilized DDB2 by inhibiting its ubiquitination, thereby promoting DDB2 localization to cyclobutane pyrimidine dimer (CPD) crosslinks to govern their repair. Such an effect was independent of the methyltransferase activity of EZH2.

In addition to its known roles in transcriptional activation, EZH2 may also silence gene expression by regulating gene promoter activity, resulting in inactivation of tumor suppressor. In MYC‐driven prostate cancer, EZH2 inhibits the expression of IFNGR1 by binding to the promoter of interferon‐γ receptor 1 (IFNGR1). This leads to the suppression of the IFN‐JAK‐STAT1 signaling pathway thereby promoting cancer development. Further research confirmed that the function of EZH2 does not depend on its H3K27 methylase activity. 58

In short, numerous evidences support the hypothesis that EZH2 acts as a "bifunctional molecule". In different organisms or in different tissues, EZH2 and other subunits of the PRC2 complex exhibit distinct patterns of behavior in different cancer types. It is suggested that EZH2 could act as a transcriptional inhibitor or a transcriptional activator. 59

5. EZH2 AS A CANCER THERAPEUTIC TARGET

Given that EZH2 plays a vital role in cancer cell proliferation, migration, invasion, and other cellular processes, EZH2 is considered to be a potential therapeutic target in cancer. The anticancer therapy which targets EZH2 is mainly achieved by inhibiting the methyltransferase activity of EZH2. S‐adenosyl methionine (SAM) is a universal methyl group donor which carries an activated methyl and participates in biological methylation reactions. 60 Multiple EZH2‐specific SAM‐competitive inhibitors, such as GSK126, GSK343, GSK926, EI1, EPZ‐005687, EPZ‐011989, EPZ‐6438, UNC‐1999, and CPI‐169, have been developed. 20

However, Kim et al reported that EZH2 enzymatic inhibitors could not completely suppress the oncogenic activity of EZH2 in SWI/SNF mutant cancers unless they were capable of disrupting the protein interactions of the PRC2 complex. 61 It indicated that dependence upon EZH2 for cancer progression can be derived from both methylase‐dependent and methylase‐independent functions of EZH2. Thus, further research is required for the development of the novel EZH2 inhibitors for the blockade of the catalytic and noncatalytic activity of EZH2. Recently, Zhou et al performed two high‐throughput screening (HTS) campaigns targeting the catalytic and noncatalytic activity of EZH2. They identified several compounds which can efficiently act against the catalytic EZH2 Y641F mutant (gain‐of‐function mutation of EZH2) or EZH2‐EED interaction, respectively. 62

3‐deazaneplanocin A (DZNep), which is an inhibitor of S‐adenosylhomocysteine, acts as a competitive EZH2 inhibitor. At present, DZNep is widely used in in vivo studies and shows effective anticancer activities in a variety of cancers. Tan et al reported that DZNep could effectively deplete cellular levels of PRC2 component EZH2, which led to apoptotic cell death in cancer cells. 63 Novel strategies to inhibit EZH2 by protein degradation have been developed. Proteolysis‐targeted chimeras (PROTACs) are molecules designed to recruit a target protein to an E3 ligase, thereby inducing ubiquitination and degradation of specific pathological proteins. 64 Accumulated PROTAC compounds targeting EZH2 for degradation, such as AM29‐117A, MS1943, PROTAC 1, and GNA002, have been developed. 65 Using these compounds, researchers claimed to induce the degradation of EZH2, resulting in broad and striking effects on cancer cell growth. Thus, it is expected that multiple approaches which target both the catalytic and noncatalytic activity of EZH2 represent a wealth of therapeutic options for cancer patients.

6. CONCLUSION

Numerous studies demonstrated that overexpression of EZH2 is associated with the invasive growth and poor prognosis of many human cancers. EZH2 participates in gene expression regulation mainly through epigenetic machinery. Studies in the last decade have shown that EZH2 could also act as a PRC2‐independent transcriptional activator. Herein, we summarized multiple methylation‐independent functions of EZH2 in cancer, including transcriptional activation, modification of nonhistone substrates, and post‐transcriptional regulation. Moreover, the diverse involvement of EZH2 is mainly dependent on cellular context and cancer types.

Therefore, future studies focusing on the regulation of EZH2 will provide insights into pathogenesis and are necessary for the development of novel anticancer therapeutic strategies targeting EZH2 in a variety of human cancers. Given the emerging noncanonical role of EZH2, it will be important to develop drugs that depend on its enzymatic activity and nonenzymatic function.

CONFLICT OF INTEREST

The authors have no conflict of interest to declare.

ACKNOWLEDGMENTS

This work was supported by grants from the National Natural Science Foundation of China to TZ (No. 31970173) and ZJ (No. 31970755), and grants from the Natural Science Foundation of Zhejiang Province to TZ (No. LY21C010001) and ZJ (No. LY21C120001).

Huang J, Gou H, Yao J, et al. The noncanonical role of EZH2 in cancer. Cancer Sci. 2021;112:1376–1382. 10.1111/cas.14840

Huang and Gou contributed equally to this work.

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