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PubMed2006

Expression of the enhancer of zeste homolog 2 is correlated with poor prognosis in human gastric cancer.

Overexpression of the enhancer of zeste homolog 2 (EZH2) protein, a known repressor of gene transcription, has been reported to be associated with biological malignancy of prostate cancer and several other cancers. The purpose of this study was to examine the expression of EZH2 and analyze its relationship with the clinicopathological features of human gastric cancers. Expression levels of EZH2 mRNA and protein were examined in 13 gastric cancer cell lines and in 83 surgically removed human gastric cancer tissues. Immunohistochemical analysis of the 83 tissue samples and corresponding non-cancerous gastric mucosa showed that EZH2 was more highly expressed in the cancerous than in the non-cancerous tissues, and the expression levels of EZH2 were highly correlated with tumor size, depth of invasion, vessel invasion, lymph node metastasis and clinical stages. Univariate analysis of survival rate calculated by the Kaplan-Meier method revealed that gastric cancer patients with high-level EZH2 expression had poorer prognosis than those expressing no or low levels of EZH2 (P = 0.0271). These findings suggest that overexpression of EZH2 may contribute to the progression and oncogenesis of human gastric cancers, and thus immunohistochemical study of EZH2 expression may serve as a new biomarker for predicting the prognosis of gastric cancers.

Aged↗
PubMed2006

Immunohistochemical evaluation of pRb2/p130, VEGF, EZH2, p53, p16, p21waf-1, p27, and PCNA in Barrett's esophagus.

Control of the G1/S-phase transition as well as angiogenic switch are two of the most studied mechanisms in cancer. The current study examined the correlation between the immunohistochemical expression of pRb2/p130, VEGF, EZH2, p53, p16, p21waf-1, p27, and PCNA in Barrett's esophagus (BE). Overall, p53 showed a much higher expression in BE patients (up to 50%) than in controls (1-10%) (P < 0.005). Also p21 showed a downregulation in BE when compared to normal esophagus (70% of cells vs. 65%), but the difference did not show any statistical significance (P = 0.45). pRb2/p130 was detected in 80% of cells in normal controls, but showed positive in only 20% of cells in BE biopsies. Additionally, Rb2/p130 expression was inversely correlated to that of VEGF, EZH2, and PCNA (P < 0.0001, P = 0.0032, P < 0.001, respectively). p27 stained more intensely and in a widespread manner (70%) cells in normal esophageal tissues but about only 30% in BE samples (P < 0.001). Lastly, in accordance with other reports, we also found p16 expressed by immunohistochemistry at high levels in normal controls and at low levels in BE (P < 0.001). In conclusion, p16, p21, p27, and p53 staining confirmed previously published data. Interestingly, pRb2/p130 expression was found significantly decreased in metaplastic epithelium compared to normal controls and showed significant inverse correlation with the expression of other markers, such as VEGF, EZH2, and PCNA. These data, taken together, indicate that these molecular events occurring in Barrett's metaplasia (BM) may represent one of the many steps taking place during esophageal malignant progression such as impairment of cell-cycle control, altered differentiation, and unbalanced angiogenesis.

Aged↗
PubMed1999

Transcriptional repression mediated by the human polycomb-group protein EED involves histone deacetylation.

Polycomb-group (PcG) proteins form multimeric protein complexes, which are involved in maintaining the transcriptional repressive state of genes over successive cell generations. Components of PcG complexes and their mutual interactions have been identified and analysed through extensive genetic and biochemical analyses. Molecular mechanisms underlying PcG-mediated repression of gene activity, however, have remained largely unknown. Previously we reported the existence of two distinct human PcG protein complexes. The EED/EZH protein complex contains the embryonic ectoderm development (EED) and enhancer of zeste 2 (EZH2; refs 9,10) PcG proteins. The HPC/HPH PcG complex contains the human polycomb 2 (HPC2; ref. 11), human polyhomeotic (HPH), BMI1 (ref. 13 ) and RING1 (refs 14, 15) proteins. Here we show that EED (refs 4, 5, 6, 7, 8) interacts, both in vitro and in vivo, with histone deacetylase (HDAC) proteins. This interaction is highly specific because the HDAC proteins do not interact with other vertebrate PcG proteins. We further find that histone deacetylation activity co-immunoprecipitates with the EED protein. Finally, the histone deacetylase inhibitor trichostatin A (ref. 17) relieves transcriptional repression mediated by EED, but not by HPC2, a human homologue of polycomb. Our data indicate that PcG-mediated repression of gene activity involves histone deacetylation. This mechanistic link between two distinct, global gene repression systems is accomplished through the interaction of HDAC proteins with a particular PcG protein, EED.

Acetylation↗
PubMed2005

EZH2 expression is associated with high proliferation rate and aggressive tumor subgroups in cutaneous melanoma and cancers of the endometrium, prostate, and breast.

PURPOSE: EZH2 is a member of the polycomb group of genes and important in cell cycle regulation. Increased expression of EZH2 has been associated previously with invasive growth and aggressive clinical behavior in prostate and breast cancer, but the relationship with tumor cell proliferation has not been examined in human tumors. The purpose of this study was to validate previous findings in a population-based setting, also including tumors that have not been studied previously. PATIENTS AND METHODS: In our study of nearly 700 patients, we examined EZH2 expression and its association with tumor cell proliferation and other tumor markers, clinical features, and prognosis in cutaneous melanoma and cancers of the endometrium, prostate, and breast. RESULTS: Strong EZH2 expression was associated with increased tumor cell proliferation in all four cancer types. Associations were also found between EZH2 and important clinicopathologic variables. EZH2 expression showed significant prognostic impact in melanoma, prostate, and endometrial carcinoma in univariate survival analyses, and revealed independent prognostic importance in carcinoma of the endometrium and prostate. CONCLUSION Our findings point at EZH2 as a novel and independent prognostic marker in endometrial cancer, and validate previous findings on prostate and breast cancer. Further, EZH2 expression was associated with features of aggressive cutaneous melanoma. The fact that EZH2 might identify increased tumor cell proliferation and aggressive subgroups in several cancers may be of practical interest because the polycomb group proteins have been suggested as candidates for targeted therapy. EZH2 expression should, therefore, be further examined as a possible predictive factor.

Biomarkers, Tumor↗
PubMed2005

The Polycomb group protein EZH2 impairs DNA repair in breast epithelial cells.

The Polycomb group protein EZH2 is a transcriptional repressor involved in controlling cellular memory and has been linked to aggressive and metastatic breast cancer. Here we report that EZH2 decreased the expression of five RAD51 paralog proteins involved in homologous recombination (HR) repair of DNA double-strand breaks (RAD51B/RAD51L1, RAD51C/RAD51L2, RAD51D/RAD51L3, XRCC2, and XRCC3), but did not affect the levels of DMC1, a gene that only functions in meiosis. EZH2 overexpression impaired the formation of RAD51 repair foci at sites of DNA breaks. Overexpression of EZH2 resulted in decreased cell survival and clonogenic capacity following DNA damage induced independently by etoposide and ionizing radiation. We suggest that EZH2 may contribute to breast tumorigenesis by specific downregulation of RAD51-like proteins and by impairment of HR repair. We provide mechanistic insights into the function of EZH2 in mammalian cells and uncover a link between EZH2, a regulator of homeotic gene expression, and HR DNA repair. Our study paves the way for exploring the blockade of EZH2 overexpression as a novel approach for the prevention and treatment of breast cancer.

Breast↗
PubMed2005

Increased expression of the polycomb group gene, EZH2, in transitional cell carcinoma of the bladder.

PURPOSE: The Polycomb group gene, EZH2, functions as a transcriptional repressor involved in gene silencing. Amplification of EZH2 has been reported in several malignancies, including prostate, breast, and lymphoma. We evaluated EZH2 mRNA and protein expression in bladder specimens from patients and the EZH2 mRNA expression in five bladder cancer cell lines. EXPERIMENTAL DESIGN: EZH2 mRNA expression was assessed by reverse transcription-PCR (RT-PCR) in 38 bladder tissue specimens. We also evaluated 39 bladder cancer specimens for EZH2 protein expression using immunohistochemistry with affinity-purified antibodies to human EZH2. In addition, five human bladder cancer cell lines were analyzed by RT-PCR for EZH2 mRNA expression. RESULTS: Five of 14 (36%) nontumor bladder specimens versus 21 of 24 (88%) bladder tumors showed EZH2 mRNA expression (P=0.003). All of the invasive tumors (10 of 10) had detectable EZH2 mRNA expression, compared with 11 of 14 (79%) superficial tumors. In addition, EZH2 mRNA expression was noted in 100% (16 of 16) of high-grade bladder tumors versus 50% (4 of 8) of low-grade tumors (P=0.01). EZH2 protein expression, meanwhile, was increased in neoplastic tissue compared with nontumor urothelium (78% versus 69% of nuclei, P<0.005). There were no differences in EZH2 protein levels between superficial and invasive tumors. High-grade tumors had increased EZH2 staining compared with normal urothelium (78% versus 68%, P<0.005), whereas low-grade lesions did not. Four of five human bladder cancer cell lines expressed high levels of EZH2, whereas only low levels were detected in one cell line. CONCLUSIONS: We report a significant increase in EZH2 expression in transitional cell carcinoma of the bladder compared with normal urothelium. These data suggest that similar to other human malignancies, increased EZH2 expression correlates with oncogenesis of the bladder.

Adult↗
PubMed2005

Clinicopathological significance of EZH2 mRNA expression in patients with hepatocellular carcinoma.

Enhancer of zeste homologue 2 (EZH2), a member of the polycomb group protein family, plays a crucial role in the regulation of embryonic development and has been associated with the regulation of the cell cycle. Recently, several studies have shown that EZH2 is highly expressed in aggressive tumours, including human breast cancer, prostate cancer, and lymphomas. We thus analysed EZH2 expression using real-time reverse transcription-polymerase chain reaction, and correlated its expression status with various clinicopathological parameters in 66 patients with hepatocellular carcinoma (HCC). We found high expression of EZH2 in human liver cancer cell lines. Furthermore, EZH2 gene-expression levels in tumour tissue specimens (0.34+/-0.52) were significantly higher (P<0.0001) than those in the corresponding nontumour tissue specimens (0.07+/-0.09). The incidence of cancer cell invasion into the portal vein was significantly higher (P<0.001) in the high EZH2 expression group (26 of the 33, 79%) than in the low expression group (13 of the 33, 39%). However, there was no significant difference in the disease-free survival rate between the two groups. The findings of this study indicate that EZH2 mRNA expression was upregulated in human HCC and may play an important role in tumour progression, especially by facilitating portal vein invasion.

Aged↗
PubMed2005

Expression levels of the EZH2 polycomb transcriptional repressor correlate with aggressiveness and invasive potential of bladder carcinomas.

The polycomb group protein enhancer of zeste 2 (EZH2) is a transcriptional repressor involved in the control of cellular proliferation and oncogenesis. The aim of the present study was to quantify EZH2 expression in bladder carcinomas and to correlate the data with clinicopathological findings. EZH2 mRNA expression was measured by real-time reverse transcription-polymerase chain reaction in tumor tissue specimens obtained from 37 patients with urothelial carcinomas of the bladder and in four bladder cancer cell lines. EZH2 levels were normalized to expression of the housekeeping porphobilinogen deaminase gene. EZH2 transcripts were commonly detected in tumor tissue. Transcript levels correlated significantly with the invasiveness of bladder tumors (p = 0.029) with elevated EZH2 mRNA expression measured in invasive bladder carcinomas (median value, 38.92) compared with non-invasive tumors (15.51). In addition, levels of expression were significantly higher in high-grade (G3) than in low-grade (G1/2) lesions (p < 0.001). EZH2 mRNA levels in bladder carcinoma cell lines were within the range of high-grade invasive bladder cancers. In conclusion, expression levels of EZH2 are elevated in aggressive and invasive urothelial carcinomas, suggesting that deregulated EZH2 expression may be involved in the progression of bladder tumors.

Aged↗
PubMed2005

Mutation screen and association study of EZH2 as a susceptibility gene for aggressive prostate cancer.

BACKGROUND: Several linkage studies have provided evidence for a prostate cancer aggressiveness gene on chromosome 7q. This report details the results of the first mutation screen and association study of EZH2 (located at 7q35) as a potential candidate gene for the development of aggressive prostate cancer. METHODS: In 10 families with linkage of chromosome 7q31-33 to aggressive prostate cancer, we sequenced the promoter region and all 20 exons of EZH2. We genotyped 11 variants in 287 prostate cancer probands and 96 controls. Association between the disease and the variants/haplotypes was evaluated taking into account clinical data and disease recurrence. RESULTS: The individual variation sites did not show significant differences in the allele frequencies between cases and controls. In contrast, one haplotype had a higher frequency in controls, and another haplotype was significantly more frequent in cases with low grade tumors (GI/II) and progression free survival (NED). CONCLUSION: We have possibly identified haplotypes which mark alleles that have a beneficial effect on the development of prostate cancer. Moreover, our results suggest that genetic variations of the EZH2 gene are not responsible for the linkage of 7q to aggressive prostate cancer.

Adult↗
PubMed2005

The human tumor antigen PRAME is a dominant repressor of retinoic acid receptor signaling.

Retinoic acid (RA) induces proliferation arrest, differentiation, and apoptosis, and defects in retinoic acid receptor (RAR) signaling have been implicated in cancer. The human tumor antigen PRAME is overexpressed in a variety of cancers, but its function has remained unclear. We identify here PRAME as a dominant repressor of RAR signaling. PRAME binds to RAR in the presence of RA, preventing ligand-induced receptor activation and target gene transcription through recruitment of Polycomb proteins. PRAME is present at RAR target promoters and inhibits RA-induced differentiation, growth arrest, and apoptosis. Conversely, knockdown of PRAME expression by RNA interference in RA-resistant human melanoma restores RAR signaling and reinstates sensitivity to the antiproliferative effects of RA in vitro and in vivo. Our data suggest that overexpression of PRAME frequently observed in human cancers confers growth or survival advantages by antagonizing RAR signaling.

Animals↗
PubMed2006

Expression of enhancer of zeste homologue 2 is significantly associated with increased tumor cell proliferation and is a marker of aggressive breast cancer.

The polycomb group protein enhancer of zeste homologue 2 (EZH2) has been linked to invasive properties of aggressive breast cancer. In this report, tissue microarray analysis of 190 breast carcinomas from a nested case-control study shows that EZH2 is significantly associated with interval breast cancers. Further, a strong relationship was found with tumor cell proliferation (by Ki-67 expression), locally advanced disease, metastasis at presentation, markers of the basal epithelial phenotype (positivity for cytokeratin 5/6 or P-cadherin), and p53 status. EZH2 expression was also significantly associated with glomeruloid microvascular proliferation, an aggressive angiogenic phenotype. For prediction of aggressive disease (any event of locally advanced disease, lymph node spread, or distant spread), EZH2 was the only variable of significance in multivariate analysis, whereas no additional information was given by Ki-67. Although EZH2 expression was significant in univariate survival analysis, only tumor cell proliferation and lymph node status were significant in the final multivariate model. In conclusion, our findings indicate an important relationship not only between EZH2 and markers of tumor cell proliferation but also with aggressive disease. These findings might be practically important and relevant because the polycomb group proteins have recently been suggested as candidates for targeted therapy.

Analysis of Variance↗
PubMed2006

Genome-wide mapping of Polycomb target genes unravels their roles in cell fate transitions.

The Polycomb group (PcG) proteins form chromatin-modifying complexes that are essential for embryonic development and stem cell renewal and are commonly deregulated in cancer. Here, we identify their target genes using genome-wide location analysis in human embryonic fibroblasts. We find that Polycomb-Repressive Complex 1 (PRC1), PRC2, and tri-methylated histone H3K27 co-occupy >1000 silenced genes with a strong functional bias for embryonic development and cell fate decisions. We functionally identify 40 genes derepressed in human embryonic fibroblasts depleted of the PRC2 components (EZH2, EED, SUZ12) and the PRC1 component, BMI-1. Interestingly, several markers of osteogenesis, adipogenesis, and chrondrogenesis are among these genes, consistent with the mesenchymal origin of fibroblasts. Using a neuronal model of differentiation, we delineate two different mechanisms for regulating PcG target genes. For genes activated during differentiation, PcGs are displaced. However, for genes repressed during differentiation, we paradoxically find that they are already bound by the PcGs in nondifferentiated cells despite being actively transcribed. Our results are consistent with the hypothesis that PcGs are part of a preprogrammed memory system established during embryogenesis marking certain key genes for repressive signals during subsequent developmental and differentiation processes.

Carrier Proteins↗
PubMed2004

Identification of polycomb group protein enhancer of zeste homolog 2 (EZH2)-derived peptides immunogenic in HLA-A24+ prostate cancer patients.

BACKGROUND: Antigens overexpressed in metastatic prostate cancer are appropriate targets in anti-cancer immunotherapy, and one candidate is the polycomb group protein enhancer of zeste homolog 2 (EZH2). METHODS: Eleven EZH2-derived peptides were prepared based on the HLA-A24 binding motif. These peptide candidates were screened first by their ability to be recognized by immunoglobulin G (IgG), and then by their ability to induce peptide-specific cytotoxic T lymphocytes (CTLs). RESULTS: IgGs reactive to three EZH2 peptides (EZH2-243 to -252, EZH2-291 to -299, and EZH2-735 to -;742) were detected in the plasma of almost half of prostate cancer patients. Among them, the EZH2-291 to -299 and EZH2-735 to -742 peptides effectively induced HLA-A24-restricted and prostate cancer-reactive CTLs from prostate cancer patients. The cytotoxicity was mainly dependent on EZH2 peptide-specific and CD8+ T cells. CONCLUSIONS: These EZH2-291 to -299 and EZH2-735 to -742 peptides could be promising candidates for peptide-based immunotherapy for HLA-A24+ prostate cancer patients with metastases.

Antibodies↗
PubMed2006

Enhancer of Zeste 2 as a marker of preneoplastic progression in the breast.

Amplification of the Polycomb group transcriptional repressor Enhancer of Zeste 2 (EZH2) occurs in various malignancies including breast cancer, where its overexpression is associated with poor outcome. We found that EZH2 is up-regulated in ductal carcinoma in situ, atypical ductal hyperplasia, and even morphologically normal breast epithelial cells from women who have an increased risk of breast cancer. This review discusses how EZH2 may promote neoplastic conversion and it surveys the evidence suggesting that EZH2 may offer a clinical tool to help identify patients at risk for developing breast cancer before precursor lesions are histologically evident.

Biomarkers↗
PubMed2005

The Polycomb group gene Ezh2 prevents hematopoietic stem cell exhaustion.

The molecular mechanism responsible for a decline of stem cell functioning after replicative stress remains unknown. We used mouse embryonic fibroblasts (MEFs) and hematopoietic stem cells (HSCs) to identify genes involved in the process of cellular aging. In proliferating and senescent MEFs one of the most differentially expressed transcripts was Enhancer of zeste homolog 2 (Ezh2), a Polycomb group protein (PcG) involved in histone methylation and deacetylation. Retroviral overexpression of Ezh2 in MEFs resulted in bypassing of the senescence program. More importantly, whereas normal HSCs were rapidly exhausted after serial transplantations, overexpression of Ezh2 completely conserved long-term repopulating potential. Animals that were reconstituted with 3 times serially transplanted control bone marrow cells all died due to hematopoietic failure. In contrast, similarly transplanted Ezh2-overexpressing stem cells restored stem cell quality to normal levels. In a "genetic genomics" screen, we identified novel putative Ezh2 target or partner stem cell genes that are associated with chromatin modification. Our data suggest that stabilization of the chromatin structure preserves HSC potential after replicative stress.

Animals↗
PubMed2006

The polycomb group protein EZH2 is required for mammalian circadian clock function.

We examined the importance of histone methylation by the polycomb group proteins in the mouse circadian clock mechanism. Endogenous EZH2, a polycomb group enzyme that methylates lysine 27 on histone H3, co-immunoprecipitates with CLOCK and BMAL1 throughout the circadian cycle in liver nuclear extracts. Chromatin immunoprecipitation revealed EZH2 binding and di- and trimethylation of H3K27 on both the Period 1 and Period 2 promoters. A role of EZH2 in cryptochrome-mediated transcriptional repression of the clockwork was supported by overexpression and RNA interference studies. Serum-induced circadian rhythms in NIH 3T3 cells in culture were disrupted by transfection of an RNA interfering sequence targeting EZH2. These results indicate that EZH2 is important for the maintenance of circadian rhythms and extend the activity of the polycomb group proteins to the core clockwork mechanism of mammals.

ARNTL Transcription Factors↗
PubMed2025

EZH2 variants derived from cryptic splice sites govern distinct epigenetic patterns during embryonic development.

EZH2 catalyzes H3K27me3&#xa0;and is essential for embryonic development. Although multiple EZH2 variants have been identified, the functional implications and physiological significance of its heterogeneity remain unclear. Here, we revealed that conserved cryptic splice sites generated two EZH2 variants with (EZH2A) or without (EZH2B) a 27-nt region, coding for a 9-aa segment. Structural modeling showed that splice-in or splice-off of the 9-aa segment caused a topological change in EZH2 structure. The 9-aa surplus in EZH2A strengthened its interaction with other PRC2 components, particularly in PRC2.2 holocomplex. We developed point-mutation mouse lines specifically depleting EZH2A or EZH2B (Ezh2amut or Ezh2bmut). Biallelic deletion of Ezh2a caused developmental defects and embryonic lethality between E12.5 and E15.5, while the Ezh2bmut mice were fertile and developed normally. Combined RNA-seq and CUT&Tag analyses in mouse embryonic fibroblasts revealed that EZH2A and EZH2B bound to different genomic loci and affected H3K27me3 deposition in different subsets of genes related to development or the innate immune system, respectively. EZH2A depletion specifically suppressed the expression of genes involved in the development-related Hippo-Yap1 pathway, which might be attributable to a compensatory process mediated by JARID2. Our findings demonstrate that EZH2 heterogeneity from the 9-aa splicing event plays a crucial role in development.

Animals↗