Polycomb group (PcG) proteins are a family of epigenetic regulators responsible for the repression of genes in proliferation and differentiation of stem cells. PcG protein complex consists of two important epigenetic regulators: PRC1 (polycomb repressive complex 1) and PRC2 (polycomb repressive complex 2). In order to further understand the functions of PcG proteins in stem cell growth and differentiation, we review the PcG protein composition, PcG protein localization in the target gene, PcG protein recruitment, and the functions of PcG proteins in the development of stem cells.
Cell Differentiation ; physiology ; Cell Proliferation ; Humans ; Polycomb Repressive Complex 1 ; metabolism ; physiology ; Polycomb Repressive Complex 2 ; metabolism ; physiology ; Polycomb-Group Proteins ; metabolism ; physiology ; Stem Cells ; cytology ; metabolism

Adult ; Enhancer of Zeste Homolog 2 Protein ; Female ; Humans ; Leukemia, Myeloid, Acute ; genetics ; Male ; MicroRNAs ; genetics ; Polycomb Repressive Complex 2 ; genetics

OBJECTIVEThis article aimed to review the biological characteristics of enhancer of zests homolog 2 (EZH2), and the transcriptional repression mechanism of action of EZH2 in tumors, particularly in the progression of lymphoma.

DATA SOURCESThe data cited in this review were mainly obtained from the articles listed in PubMed and HighWare that were published from March 2004 to April 2012. The search terms were "enhancer of zests homolog 2", "polycomb group", and "lymphoma".

STUDY SELECTIONArticles regarding the mechanism of EZH2 in post-transcriptional modification, functions of polycomb group proteins, and the roles of EZH2 in lymphoma were selected.

RESULTSEZH2 acts as oncogene and involved in many kinds of tumors. Moreover, it plays an important role in tumorigenesis and lymphomagenesis by promoting the proliferation and aggressiveness of neoplastic cells, facilitating malignant tumor cell diffusion, and mediating transcriptional silencing.

CONCLUSIONEZH2 mediated transcriptional repression through its methyltransferase activity at the chromatin level has certain influence on lymphoma, and there might exist a therapeutic window for the development of new agents and identification of novel diagnostic markers based on EZH2.

Disease Progression ; Enhancer of Zeste Homolog 2 Protein ; Epigenesis, Genetic ; Histones ; metabolism ; Humans ; Lymphoma ; etiology ; genetics ; Methylation ; Mutation ; Polycomb Repressive Complex 2 ; genetics ; physiology

OBJECTIVETo investigate the effect of miRNA-101 on the expression of the enhancer of zeste homolog 2 (EXH2) in human androgen-independent prostated cancer LNCaP cells.

METHODSWe divided LNCaP cells into a blank control, a negative control, and a miRNA-l01 transfection group, constructed the vector by transfecting synthetic miRNA-101 mimics into the LNCaP cells, and evaluated the efficiency of transfection by fluorescence microscopy. Then we determined the expression level of EZH2 mRNA by qRT-PCR in the three groups of cells and that of the EZH2 protein in the negative control and transfection groups by Western blot.

RESULTSGreen fluorescence signals were observed in over 70% of the LNCaP cells in the transfection group after 24 hours of transfection. At 72 hours, the expression of miRNA-101 was significantly upregulated in the transfected cells (P < 0.01), that of EZH2 mRNA was remarkably lower in the transfection group (0.01 ± 0.10) than in the blank control (0.95 ± 0.40) and negative control (0.86 ± 0.30) groups (both P < 0.01), and that of the EZH2 protein was increased in the negative control but decreased in the transfection group with the extension of culture time.

CONCLUSIONmiRNA-101, with its inhibitory effect on the expression of EZH2 in LNCaP cells, is a potential biotherapeutic for prostate cancer.

Androgens ; Cell Line, Tumor ; Enhancer of Zeste Homolog 2 Protein ; Genetic Vectors ; Humans ; Male ; MicroRNAs ; physiology ; Polycomb Repressive Complex 2 ; genetics ; metabolism ; Prostatic Neoplasms ; metabolism ; RNA, Messenger ; metabolism ; Transfection

OBJECTIVETo investigate the expression of enhancer of zeste homolog 2 (EZH2) in esophageal squamous cell carcinoma and its association with the prognosis of postoperative patients.

METHODSSurgical specimens were obtained from 102 patients with esophageal squamous cell carcinoma undergoing radical resection in our hospital from 1996 to 2006. Immunochemistry was employed to examine EZH2 protein expressions in the specimens, including 102 carcinoma tissue specimens, 30 adjacent tissue specimens and 30 normal esophageal tissue specimens. The expression levels of EZH2 were analyzed in relation to the clinicopathological parameters of the patients including gender, age, tumor differentiation, TNM, and lymph node metastasis. The postoperative patients were followed up to analyze the association of EZH2 expression with the clinical outcomes.

RESULTSThe esophageal squamous cell carcinoma tissue showed a higher EZH2 expression than the adjacent and normal esophageal tissues. EZH2 expression was higher in poorly differentiated carcinoma than in well differentiated tissue, and also higher in cases with lymph node metastasis than those without; the expression was higher in TNM stage II/III patients than in stage I patients but lower than in stage IV patients. The patients with low EZH2 expression was found to have a longer survival time than those with high EZH2 expression (P<0.05).

CONCLUSIONEZH2 plays an important role in the differentiation and metastasis of esophageal squamous cell carcinoma, and a high EZH2 expression is associated with a poor outcome in the the postoperative patients.

Carcinoma, Squamous Cell ; diagnosis ; metabolism ; Enhancer of Zeste Homolog 2 Protein ; Esophageal Neoplasms ; diagnosis ; metabolism ; Humans ; Lymphatic Metastasis ; Polycomb Repressive Complex 2 ; metabolism ; Postoperative Period ; Prognosis

OBJECTIVETo screen novel miRNAs targeting EZH2 3' untranslated region (UTR) in recombinational MCF-7 breast cancer cells over-expressing EZH2 3' UTR and quantitative analyze the expressions of the screened miRNA in breast cancer cells and tissues.

METHODSA lentiviral library was transfected into the recombinant cell line MCF-7. The cells were screened with cytotoxic agents before extraction of the genome for amplification of the miRNA precursors using PCR. The screened miRNAs were identified with sequence analysis and their expressions were analyzed quantitatively with real-time PCR in breast cancer cells and tissues.

RESULTSSeven miRNAs were screened from the recombinant MCF-7 cells, namely miR-15b, miR-16-2, miR-181b2, miR-217, miR-224, miR-329-1, and miR-487b, all of which failed to be predicted by bioinformatics software. Real-time PCR showed that miR-217, miR-329-1, and miR-487b were over-expressed in MCF-7 cells, and the expression of miR-15b and miR-16-2 was significantly increased in cancer tissues compared with the adjacent tissues (P<0.05).

CONCLUSIONNovel targeted miRNAs that can not be predicted by bioinformatics software were successfully screened from MCF-7 breast cancer cells over-expressing EZH2 3' UTR. These miRNAs are expressed differentially between normal breast cells and breast cancer tissues.

3' Untranslated Regions ; Breast Neoplasms ; genetics ; Cell Line, Tumor ; Enhancer of Zeste Homolog 2 Protein ; Female ; Gene Expression Profiling ; Humans ; Lentivirus ; genetics ; MicroRNAs ; genetics ; Polycomb Repressive Complex 2 ; genetics

Epigenetic alterations are associated with all aspects of cancer, from tumor initiation to cancer progression and metastasis. It is now well understood that both losses and gains of DNA methylation as well as altered chromatin organization contribute significantly to cancer-associated phenotypes. More recently, new sequencing technologies have allowed the identification of driver mutations in epigenetic regulators, providing a mechanistic link between the cancer epigenome and genetic alterations. Oncogenic activating mutations are now known to occur in a number of epigenetic modifiers (i.e. IDH1/2, EZH2, DNMT3A), pinpointing epigenetic pathways that are involved in tumorigenesis. Similarly, investigations into the role of inactivating mutations in chromatin modifiers (i.e. KDM6A, CREBBP/EP300, SMARCB1) implicate many of these genes as tumor suppressors. Intriguingly, a number of neoplasms are defined by a plethora of mutations in epigenetic regulators, including renal, bladder, and adenoid cystic carcinomas. Particularly striking is the discovery of frequent histone H3.3 mutations in pediatric glioma, a particularly aggressive neoplasm that has long remained poorly understood. Cancer epigenetics is a relatively new, promising frontier with much potential for improving cancer outcomes. Already, therapies such as 5-azacytidine and decitabine have proven that targeting epigenetic alterations in cancer can lead to tangible benefits. Understanding how genetic alterations give rise to the cancer epigenome will offer new possibilities for developing better prognostic and therapeutic strategies.
Chromatin ; metabolism ; Chromatin Assembly and Disassembly ; DNA Methylation ; Enhancer of Zeste Homolog 2 Protein ; Epigenesis, Genetic ; Histones ; metabolism ; Humans ; Neoplasms ; genetics ; metabolism ; pathology ; Polycomb Repressive Complex 2 ; genetics ; metabolism

PURPOSE: The enhancer of zeste homologue 2 (EZH2) is a catalytic subunit of the polycomb repressive complex 2, a highly conserved histone methyltransferase. EZH2 overexpression has been implicated in various malignancies, including breast cancer, where is associated with poor outcomes. This study aims to clarify nuclear EZH2 expression levels in breast cancers using immunohistochemistry (IHC) and correlate these findings with clinicopathologic variables, including prognostic significance. METHODS: IHC was performed on tissue microarrays of 432 invasive ductal carcinoma (IDC) tumors. Associations between EZH2 expression, clinicopathologic characteristics, and molecular subtype were retrospectively analyzed. The relationship between EZH2 protein expression in normal breast tissue and ductal carcinoma in situ (DCIS) was also assessed. RESULTS: High EZH2 expression was demonstrated in 215 of 432 tumors (49.8%). EZH2 was more frequently expressed in DCIS and IDC than in normal breast tissue (p=0.001). High EZH2 expression significantly correlated with high histologic grade (p<0.001), large tumor size (p=0.014), advanced pathologic stage (p=0.006), negative estrogen receptor status (p<0.001), positive human epidermal growth factor receptor 2 (HER2) status (p<0.001), high Ki-67 staining index (p<0.001), positive cytokeratin 5/6 status (p=0.003), positive epidermal growth factor receptor status (p<0.001), and positive p53 status (p<0.001). Based on molecular subtypes, high EZH2 expression was significantly associated with HER2-negative luminal B, HER2-positive luminal B, and HER2 type and triple-negative basal cancers (p<0.001). In patients with luminal A, there was a significant trend toward shorter overall survival for those with tumors having high EZH2 expression compared to those with tumors having low EZH2 expression (p=0.045). CONCLUSION: EZH2 is frequently upregulated in breast malignancies, and it may play an important role in cancer development and progression. Furthermore, EZH2 may be a prognostic marker, especially in patients with luminal A cancer.
Breast Neoplasms* ; Breast* ; Carcinoma, Ductal ; Carcinoma, Intraductal, Noninfiltrating ; Catalytic Domain ; Estrogens ; Histones ; Humans ; Immunohistochemistry ; Keratins ; Phenobarbital* ; Polycomb Repressive Complex 2 ; Prognosis ; Receptor, Epidermal Growth Factor ; Retrospective Studies

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.
Drug Resistance ; Epigenomics ; Gene Silencing ; Histones ; Lysine ; Methylation ; MicroRNAs ; Neoplasm Metastasis ; Polycomb Repressive Complex 2 ; Protein Processing, Post-Translational ; RNA, Untranslated ; Transcription Factors ; Transcription, Genetic

OBJECTIVETo investigate the expression of EZH2 in breast cancer and its clinicopathological significance.

METHODSEighty cases of invasive breast cancer with complete clinlcpathological data and follow-up information were enrolled in the study. The expressions of ER, PR, HER-2, CK5/6, CK14, EGFR and EZH2 proteins were detected by immunohistochemistry (IHC). The relationship of EZH2 expression with molecular subtypes and prognosis of breast cancer was analyzed.

RESULTSIn 80 cases of breast cancer, there were 49 cases of Luminal subtype, 8 cases of HER-2(+) subtype, 20 cases of Basal-like subtype and 3 cases of Normal breast-like subtype. The molecular subtypes of breast cancer were associated with menopausal status of patients. Luminal subtype had the highest overall survival rate, while the Basal-like carcinomas were associated with the lowest survival (P< 0.05). The overall EZH2-positive expression rate was 45.00% and the expression was correlated with axillary lymph node metastasis, histological grading and clinical staging of breast cancer (P < 0.05). The EZH2-positive expression rates in Luminal subtype, HER-2(+) subtype and Basal-like subtype of breast cancers were 34.6%,50.0% and 70.0%, respectively (P <0.05).

CONCLUSIONPositive expression of EZH2 may indicate a poor prognosis of breast cancer patients and it might be used as a novel therapeutic target for breast cancer of Basal-like subtype.

Adult ; Aged ; Aged, 80 and over ; Breast Neoplasms ; metabolism ; pathology ; Enhancer of Zeste Homolog 2 Protein ; Female ; Humans ; Immunohistochemistry ; Lymphatic Metastasis ; Middle Aged ; Neoplasm Grading ; Neoplasm Staging ; Polycomb Repressive Complex 2 ; metabolism ; Prognosis ; Receptor, ErbB-2 ; metabolism