Enhancer Of Zeste Homolog 2 In Cancer Research Articles

The roles of EZH2 in cancer and its inhibitors.

The enhancer of zeste homolog 2 (EZH2) is encoded by the Enhancer of zeste 2 polycomb repressive complex 2 subunit gene. EZH2 is involved in the cell cycle, DNA damage repair, cell differentiation, autophagy, apoptosis, and immunological modulation. The main function of EZH2 is to catalyze the methylation of H3 histone of H3K27Me3, which inhibits the transcription of target genes, such as tumor suppressor genes. EZH2 also forms complexes with transcriptions factors or directly binds to the promoters of target genes, leading to regulate gene transcriptions. EZH2 has been as a prominent target for cancer therapy and a growing number of potential targeting medicines have been developed. This review summarized the mechanisms that EZH2 regulates gene transcription and the interactions between EZH2 and important intracellular signaling molecules (Wnt, Notch, MEK, Akt) and as well the clinical applications of EZH2-targeted drugs.

EZH2: An Accomplice of Gastric Cancer.

Gastric cancer is the fifth most common cancer and the third leading cause of cancer deaths worldwide. Understanding the factors influencing the therapeutic effects in gastric cancer patients and the molecular mechanism behind gastric cancer is still facing challenges. In addition to genetic alterations and environmental factors, it has been demonstrated that epigenetic mechanisms can also induce the occurrence and progression of gastric cancer. 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. It has been found that EZH2 is overexpressed in the stomach, which promotes the progression of gastric cancer through multiple pathways. In addition, targeted inhibition of EZH2 expression can effectively delay the progression of gastric cancer and improve its resistance to chemotherapeutic agents. Given the many effects of EZH2 in gastric cancer, there are no studies to comprehensively describe this mechanism. Therefore, in this review, we first introduce EZH2 and clarify the mechanisms of abnormal expression of EZH2 in cancer. Secondly, we summarize the role of EZH2 in gastric cancer, which includes the association of the EZH2 gene with genetic susceptibility to GC, the correlation of the EZH2 gene with gastric carcinogenesis and invasive metastasis, the resistance to chemotherapeutic drugs of gastric cancer mediated by EZH2 and the high expression of EZH2 leading to poor prognosis of gastric cancer patients. Finally, we also clarify some of the current statuses of drug development regarding targeted inhibition of EZH2/PRC2 activity.

The noncanonical role of EZH2 in cancer.

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.

Expression of EZH2 in endometrial carcinoma and its effects on proliferation and invasion of endometrial carcinoma cells.

Expression of enhancer of zeste homolog 2 (EZH2) has been implicated in cancer pathology, but research on its mechanistic activity is limited. The present study sought to assess the levels expression of EZH2 in patients with endometrial carcinoma (EC) and to explore the effects of EZH2 downregulation on the biological behavior of endometrial carcinoma RL-952 cells. Samples were obtained from a total of 104 patients with EC and an immunohistochemical assay was used to detect the expression of EZH2 in cancer and adjacent tissues. The relationship between the expression of EZH2 and the clinicopathological features was analyzed. Endometrial carcinoma RL-952 cells were transfected with chemically synthesized siRNA to conduct targeting inhibition of EZH2 expression. The expression levels of EZH2 protein were detected by immunoblotting. MTT and Transwell assays were used to detect the changes of cell proliferation and invasion after EZH2 downregulation. Of the 104 cases of endometrial carcinoma samples, 71 cases showed positive expression of EZH2, with an expression rate of 68.27%. In 104 cases of adjacent tissue samples, 25 cases showed positive expression of EZH2, with an expression rate of 24.03%. The expression of EZH2 in endometrial carcinoma tissue was significantly higher than that in adjacent tissue (P<0.05). The expression of EZH2 in endometrial carcinoma tissue was not correlated with the menopausal status and age of patients (P>0.05), but was correlated with the histological grade, depth of tumor invasion, lymph node metastasis and TNM stage (P<0.05). The expression of E2H2 was significantly downregulated by si-E2H2 and the proliferation and invasion abilities of cells were significantly reduced after EZH2 downregulation (P<0.05). EZH2 is closely related to the development of endometrial carcinoma and can enhance the proliferative activity of endometrial carcinoma RL-952 cells and promote cell invasion.

Predicting the Correlation of EZH2 and Cancer Stem Cell Markers in Esophageal Squamous Cell Carcinoma.

Enhancer of zeste homolog 2 (EZH2), a stemness factor, plays roles in regulation of cell differentiation and embryonic development as well as cancer progression. Deregulation of EZH2 in cancers is correlated with tumor cell invasiveness, metastasis, and the patients' poor outcome. However, the mechanistic role of EZH2 in cancer is ambiguous. In this study, we aimed to inhibit the expression of EZH2 in a cancer cell line, and evaluate consequence changes in gene expression pattern. Using specific retroviral shRNA-EZH2, EZH2 gene was silenced in the KYSE30 cell line. Relative comparative real-time PCR was used to confirm silencing of EZH2 and evaluate expression pattern of selected markers. Inhibition of EZH2 expression in KYSE30 cells caused significant changes in different genes. Indeed, HIWI and HEY1 genes were over- and underexpressed in KYSE30 cells, respectively, following EZH2 silencing. Other selected cancer stem cell markers were not changed significantly. To the best our knowledge, there are variety of small molecule inhibitors to target EZH2 in cancer cells as a treatment candidate; therefore, our data in this study helps the researchers to select EZH2 for cancer therapy based on its mechanism and correlation with other markers.

Integrated bioinformatics analysis of chromatin regulator EZH2 in regulating mRNA and lncRNA expression by ChIP sequencing and RNA sequencing

Enhancer of zeste homolog 2 (EZH2), a dynamic chromatin regulator in cancer, represents a potential therapeutic target showing early signs of promise in clinical trials. EZH2 ChIP sequencing data in 19 cell lines and RNA sequencing data in ten cancer types were downloaded from GEO and TCGA, respectively. Integrated ChIP sequencing analysis and co-expressing analysis were conducted and both mRNA and long noncoding RNA (lncRNA) targets were detected. We detected a median of 4,672 mRNA targets and 4,024 lncRNA targets regulated by EZH2 in 19 cell lines. 20 mRNA targets and 27 lncRNA targets were found in all 19 cell lines. These mRNA targets were enriched in pathways in cancer, Hippo, Wnt, MAPK and PI3K-Akt pathways. Co-expression analysis confirmed numerous targets, mRNA genes (RRAS, TGFBR2, NUF2 and PRC1) and lncRNA genes (lncRNA LINC00261, DIO3OS, RP11-307C12.11 and RP11-98D18.9) were potential targets and were significantly correlated with EZH2. We predicted genome-wide potential targets and the role of EZH2 in regulating as a transcriptional suppressor or activator which could pave the way for mechanism studies and the targeted therapy of EZH2 in cancer.

Targeting EZH2 for Cancer Therapy: Progress and Perspective

Enhancer of Zeste Homolog 2 (EZH2) is the core component of the polycomb repressive complex 2 (PRC2), possessing the enzymatic activity in generating di/tri-methylated lysine 27 in histone H3. EZH2 has important roles during early development, and its dysregulation is heavily linked to oncogenesis in various tissue types. Accumulating evidences suggest a remarkable therapeutic potential by targeting EZH2 in cancer cells. The first part reviews current strategies to target EZH2 in cancers, and evaluates the available compounds and agents used to disrupt EZH2 functions. Then we provide insight to the future direction of the research on targeting EZH2 in different cancer types. We comprehensively discuss the current understandings of the 1) structure and biological activity of EZH2, 2) its role during the assembling of PRC2 and recruitment of other protein components, 3) the molecular events directing EZH2 to target genomic regions, and 4) post-translational modification at EZH2 protein. The discussion provides the basis to inspire the development of novel strategies to abolish EZH2-related effects in cancer cells.

Regulation and Role of EZH2 in Cancer.

Polycomb repressive complex 2 (PRC2) is the epigenetic regulator that induces histone H3 lysine 27 methylation (H3K27me3) and silences specific gene transcription. Enhancer of zeste homolog 2 (EZH2) is an enzymatic subunit of PRC2, and evidence shows that EZH2 plays an essential role in cancer initiation, development, progression, metastasis, and drug resistance. EZH2 expression is indeed regulated by various oncogenic transcription factors, tumor suppressor miRNAs, and cancer-associated non-coding RNA. EZH2 activity is also controlled by post-translational modifications, which are deregulated in cancer. The canonical role of EZH2 is gene silencing through H3K27me3, but accumulating evidence shows that EZH2 methlyates substrates other than histone and has methylase-independent functions. These non-canonical functions of EZH2 are shown to play a role in cancer progression. In this review, we summarize current information on the regulation and roles of EZH2 in cancer. We also discuss various therapeutic approaches to targeting EZH2.

Enhanced Gene Expression of EZH2 In Patients with Primary Myelofibrosis

AbstractAbstract 4118 Introduction:The polycomb repressive complex (PRC) 2 contains 3 core proteins, EZH2 (enhancer of zeste homolog 2), SUZ12, and EED, in which the SET (suppressor of vaegation-enhancer of zeste-trithorax) domain of EZH2 mediates the histone methyltransferase activity. This induces trimethylation of lysine 27 on histone H3, regulates the expression of HOX genes, and promotes proliferation and aggressiveness of neoplastic cells. EZH2, a known repressor of gene transcription, has been reported to be overexpressed in many cancers and correlates with poor prognosis. EZH2 may also be involved in disease progression in patients with the classical Philadelphia-negative chronic myeloproliferative neoplasms (CMPNs) encompassing essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF). Since the potential oncogenic role of EZH2 in CMPNs has never been investigated, we have assessed gene expression of EZH2 in a cohort of patients with CMPNs. Patients and Methods:Using Affymetrix HG-U133 2.0 Plus microarrays, recognizing 54675 probe sets (38500 genes), gene expression profiling has been performed on control subjects (n=21) and patients with ET (n =19), PV (n=41), and PMF (n=9). All patients were diagnosed according to the WHO criteria of a CMPN. Total RNA was purified from whole blood and amplified to biotin-labeled RNA and hybridized to microarray chips. Results:We identified 20439, 25307, 17417, and 25421 probe sets which were differentially expressed between controls and patients with ET, PV, PMF, and CPMNs as a whole, respectively (false discovery rate (FDR) adjusted p values < 0.05). These genes included EZH2, which was highly significantly upregulated in patients with PMF as compared to controls (2.3 fold upregulated; uncorrected p-value=1.09×10-8 and FDR=1.75×10-6, and between PMF and non-PMF patients (fold change=2.0, FDR < 0.0005). No significant differences in EZH2 gene expression were recorded between controls and ET patients, controls and PV patients, or controls and the CMPN group as a whole. Within patients, the EZH2 gene was also differentially expressed with the highest levels being recorded in patients with PMF compared to PV patients (fold change=2.4, FDR < 7.5 ×10-6). Discussion and Conclusions:Using global gene expression profiling we have found the EZH2 gene to be significantly upregulated in CMPN patients, with the highest expression levels being found in PMF. We hypothesize that an altered expression of EZH2 may be involved in the transformation of ET and PV into myelofibrosis. It remains to be clarified if deregulation of EZH2 occurs consequent to mutations in the EZH2-gene. Enhanced EZH2 expression may also be associated with silencing of differentiation genes during myelofibrotic and leukemic transformation. An increased expression of EZH2 may provide a proliferative advantage of the malignant clone through interaction with the pathways of key elements controlling cell growth arrest and differentiation, (e.g. nuclear factor kappa beta and - the proteasome pathway). Studies are in progress to elucidate if genomic loss of distinct microRNAs (microRNA 101 leads to overexpression of EZH2 in cancer is associated with overexpression of EZH2 in CMPNs. Highly expressed EZH2 may be a new marker of an aggressive clinical phenotype which might imply EZH2 as a novel biomarker for predicting prognosis. If so, EZH2-blockade might be a novel approach to be incorporated in the strategies for developing epigenetic therapies in patients with CMPNs. Disclosures:No relevant conflicts of interest to declare.

Genomic loss of microRNA-101 leads to overexpression of histone methyltransferase EZH2 in cancer.

Enhancer of zeste homolog 2 (EZH2) is a mammalian histone methyltransferase that contributes to the epigenetic silencing of target genes and regulates the survival and metastasis of cancer cells. EZH2 is overexpressed in aggressive solid tumors by mechanisms that remain unclear. Here we show that the expression and function of EZH2 in cancer cell lines are inhibited by microRNA-101 (miR-101). Analysis of human prostate tumors revealed that miR-101 expression decreases during cancer progression, paralleling an increase in EZH2 expression. One or both of the two genomic loci encoding miR-101 were somatically lost in 37.5% of clinically localized prostate cancer cells (6 of 16) and 66.7% of metastatic disease cells (22 of 33). We propose that the genomic loss of miR-101 in cancer leads to overexpression of EZH2 and concomitant dysregulation of epigenetic pathways, resulting in cancer progression.

Repression of E-cadherin by the polycomb group protein EZH2 in cancer

Enhancer of zeste homolog 2 (EZH2) is a critical component of the polycomb-repressive complex 2 (PRC2), which is involved in gene silencing and histone H3 lysine 27 methylation. EZH2 has a master regulatory function in controlling such processes as stem cell differentiation, cell proliferation, early embryogenesis and X chromosome inactivation. Although benign epithelial cells express very low levels of EZH2, increased levels of EZH2 have been observed in aggressive solid tumors such as those of the prostate, breast and bladder. The mechanism by which EZH2 mediates tumor aggressiveness is unclear. Here, we demonstrate that EZH2 mediates transcriptional silencing of the tumor suppressor gene E-cadherin by trimethylation of H3 lysine 27. Histone deacetylase inhibitors can prevent EZH2-mediated repression of E-cadherin and attenuate cell invasion, suggesting a possible mechanism that may be useful for the development of therapeutic treatments. Taken together, these observations provide a novel mechanism of E-cadherin regulation and establish a functional link between dysregulation of EZH2 and repression of E-cadherin during cancer progression.