Humans ; Cardiovascular Diseases ; Enhancer of Zeste Homolog 2 Protein/metabolism* ; Histones ; Methyltransferases

Humans ; Cardiovascular Diseases ; Enhancer of Zeste Homolog 2 Protein/metabolism* ; Histones ; Methyltransferases

The histone methyltransferase enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2)-mediated trimethylation of histone H3 lysine 27 (H3K27me3) regulates neural stem cell proliferation and fate specificity through silencing different gene sets in the central nervous system. Here, we explored the function of EZH2 in early post-mitotic neurons by generating a neuron-specific Ezh2 conditional knockout mouse line. The results showed that a lack of neuronal EZH2 led to delayed neuronal migration, more complex dendritic arborization, and increased dendritic spine density. Transcriptome analysis revealed that neuronal EZH2-regulated genes are related to neuronal morphogenesis. In particular, the gene encoding p21-activated kinase 3 (Pak3) was identified as a target gene suppressed by EZH2 and H3K27me3, and expression of the dominant negative Pak3 reversed Ezh2 knockout-induced higher dendritic spine density. Finally, the lack of neuronal EZH2 resulted in impaired memory behaviors in adult mice. Our results demonstrated that neuronal EZH2 acts to control multiple steps of neuronal morphogenesis during development, and has long-lasting effects on cognitive function in adult mice.
Animals ; Mice ; Enhancer of Zeste Homolog 2 Protein/metabolism* ; Histone Methyltransferases/metabolism* ; Histones/genetics* ; Morphogenesis ; Neuronal Plasticity ; Neurons/metabolism*

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

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

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

BACKGROUNDProlactin (PRL) is a pituitary polypeptide hormone characterized by multiple biological actions including stimulation of growth in the prostate and formation of secretory alveoli and stimulation of milk protein gene expression in the mammary gland. PRL exerts its effect by dimerizing its receptor (PRLR) on the plasma membrane and regulating gene expression through the JAK-Stat signal pathway. We have previously described a natural variant of the PRLR in which the S2 subdomain of the extracellular domain is missing (Delta S2). Delta S2 PRLRs are dimerized in the absence of PRL and have constitutive activity in the promotion of breast cancer cell growth. Enhancer of zeste homolog 2 (EZH2), as one of the histone-modifying enzymes, is a key factor regulating gene expression by epigenetic modification. We hypothesized that these constitutive activated Delta S2 PRLRs played a pathogenic role in breast cancer in part through alterations in the expression of EZH2 and the trimethylation of histone 3 on lysine 27 (H3K27Me3).

METHODSIn order to verify the clinical significance and to establish the link between Delta S2 PRLR expression and epigenetic change, EZH2, H3K27Me3, and Delta S2 PRLR were detected in both normal and cancerous human breast tissues. Also, overexpression of Delta S2 PRLR in breast epithelial cells was achieved by infection with adenovirus carrying the cDNA. Western blotting and chromatin immunoprecipitation (ChIP assay) and acid histone extraction were applied to detect the expression of EZH2 and the trimethylation of histone 3, respectively.

RESULTSIn breast tissue, higher EZH2 expression and higher H3K27Me3 were found associated with higher Delta S2 expression in breast cancer samples. In breast epithelial cells, overexpression of Delta S2 PRLR increased EZH2 methyltransferase mRNA and protein, induced EZH2 methyltransferase recruitment to chromatin, increased the trimethylation of H3K27Me3, and decreased the expression of p53 gene.

CONCLUSIONSDelta S2 PRLR plays an important pathogenic role in breast cancer through epigenetic modification. Elevated expression of Delta S2 PRLR, achieved by alternate splicing of the pre-mRNA of the full-length form, is a new mechanism contributing to human breast cancer.

Breast Neoplasms ; metabolism ; Enhancer of Zeste Homolog 2 Protein ; Female ; Gene Expression Regulation, Neoplastic ; Histones ; metabolism ; Humans ; MCF-7 Cells ; Polycomb Repressive Complex 2 ; metabolism ; Receptors, Prolactin ; metabolism ; Tumor Suppressor Protein p53 ; metabolism

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

OBJECTIVETo investigate the expressions of the EZH2 protein and EZH2 mRNA in human prostate cancer (PCa) and their correlation with the clinicopathologic parameters.

METHODSA tissue microarray (TMA) was constructed, which contained 48 dots of formalin-fixed paraffin-embedded tissue samples of human PCa. The expressions of the EZH2 protein and EZH2 mRNA in the samples were detected by immunohistochemistry (EnVision) and in situ hybridization (ISH). Another 15 cases of human benign prostate hyperplasia (BPH) and 12 cases of human prostate intraepithelial neoplasia (HGPIN) were taken as controls.

RESULTSThe positive rates of the EZH2 protein and mRNA were significantly higher in PCa than in BPH and HGPIN (87.5% vs 13.33% and 16.67%, 81.25% vs 6.67% and 16.67%, P < 0.05). The positive expression of the EZH2 protein was 96.67% and 72.22% in the Gleason score > or = 7 and Gleason score < or = 6 groups, respectively, with significant differences between the two groups (P < 0.05). The positivity of the EZH2 protein was significantly related to the TNM stage, increasing with tumor progression (P < 0.05), but not to age and serum PSA (P > 0.05), and so was that of EZH2 mRNA to TNM stage (P < 0.05), but not to age, serum PSA and Gleason score (P > 0.05). When the above characteristics were regarded as two-level discrete variables, both the EZH2 protein and EZH2 mRNA showed statistically significant differences in the positive expression rate (P < 0.05).

CONCLUSIONThe over-expressions of the EZH2 protein and EZH2 mRNA may play an important role in the pathogenesis and progression of PCa and provide some reference indexes for estimating the malignancy, progression and prognosis of PCa.

Aged ; Aged, 80 and over ; DNA-Binding Proteins ; genetics ; metabolism ; Enhancer of Zeste Homolog 2 Protein ; Humans ; Male ; Middle Aged ; Polycomb Repressive Complex 2 ; Prognosis ; Prostatic Hyperplasia ; metabolism ; pathology ; Prostatic Neoplasms ; metabolism ; pathology ; RNA, Messenger ; genetics ; Transcription Factors ; genetics ; metabolism