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Objective:To detect the enhancer of zeste 2 polycomb repressive complex 2 subunit ( EZH2) in glioma patients and analyze its value in disease and prognosis evaluation. Methods:Patients with glioma (glioma group, 90 cases) and patients with benign brain diseases (control group, 45 cases) in Beichen District Hospital of Traditional Chinese Medicine from January 2017 to December 2018 were selected as the research subjects. Methyl-specific PCR was employed to detect the methylation status of the EZH2 gene of the patients in the glioma group (tumor tissue, adjacent normal tissue), the control group (brain tissue), and in glioma cell lines (SHG-44, U251, U87, and CRT). The relationship between EZH2 gene unmethylation and clinicopathological factors was analyzed. The survival difference between the unmethylated and methylated EZH2 gene in tumor tissue of glioma patients was analyzed by Kaplan-Meier survival analysis. Results:The unmethylated rate of the EZH2 gene in the tumor tissue of the glioma group (68.9%) is significantly higher than that of the control group (5.6%) and in the normal tissue adjacent to the tumor (4.4%), and the differences are statistically significant (all P < 0.05). The EZH2 gene of glioma cell lines such as SHG-44, U251, U87, and CRT is unmethylated. There are significant differences in the unmethylated rate of the EZH2 gene in the tumor tissue of the glioma group in terms of intracranial hypertension, maximum tumor diameter, tumor number, and WHO grade (all P < 0.05). The unmethylated rate of the EZH2 gene in patients with intracranial hypertension, tumor maximum diameter ≥ 5 cm, multiple and grade Ⅲ + Ⅳ gliomas is significantly higher than that without intracranial hypertension, tumor maximum diameter < 5 cm, single and grade Ⅰ + Ⅱ gliomas, and the difference is statistically significant (all P < 0.05). The median survival time of EZH2 unmethylated patients is (13.45 ± 3.15) months, and the median survival time of EZH2 methylated patients is (19.45 ± 3.56) months. The median survival time of EZH2 methylated patients is significantly higher than that of unmethylated patients (Logrank = 30.084, P < 0.05). Conclusions:EZH2 is hypomethylated in glioma tumor tissue and can be used as a molecular marker for glioma disease and prognosis assessment
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Abnormal expression of polycomb repressive complex 2 (PRC2) is related to the development of a variety of diseases. Inhibition of normal or overactive PRC2 can reduce cell survival and inhibit tumor growth in several cancers. Therefore, the identification and development of small molecule inhibitors has become an active field of current epigenetic-related anti-tumor strategies. A small molecule inhibitor targeting the S-adenosyl-L-methionine (SAM) binding site of enhancer of zeste homologue 2 (EZH2) has been approved by FDA. However, acquired drug resistance is of concern. Drugs targeting two different binding sites of embryonic ectoderm development (EED) are also being developed. The development of EZH2-EED proton pump inhibitor has attracted extensive attention due to its unique mechanism of action. In this paper, we review the research progress on various small molecule inhibitors that target PRC2-related proteins to provide a basis for further research and development of related drugs.
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BACKGROUND: A long non-coding RNA hox transcript antisense intergenic RNA (HOTAIR) is involved in epigenetic regulation through chromatin remodeling by recruiting polycomb repressive complex 2 (PRC2) proteins (EZH2, SUZ12, and EED) that induce histone H3 trimethylation at lysine 27 (H3K27me3). Deregulation of c-MYC and interaction between c-MYC and EZH2 are well known in lymphomagenesis; however, little is known about the expression status of HOTAIR in diffuse large B-cell lymphomas (DLBCLs). METHODS: The expression status of PRC2 (EZH2, SUZ12, and EED), H3K27me3, c-MYC, and BCL2 was analyzed using immunohistochemistry (n = 231), and HOTAIR was investigated by a quantification real-time polymerase chain reaction method (n = 164) in DLBCLs. RESULTS: The present study confirmed the positive correlation among PRC2 proteins, H3K27me3, and c-MYC in DLBCLs. Expression level of HOTAIR was also positively correlated to EZH2 (p < .05, respectively). Between c-MYC and HOTAIR, and between c- MYC/BCL2 co-expression and HOTAIR, however, negative correlation was observed in DLBCLs (p < .05, respectively). High level of H3K27me3 was determined as an independent prognostic marker in poor overall survival (hazard ratio, 2.0; p = .023) of DLBCL patients. High expression of HOTAIR, however, was associated with favorable overall survival (p = .004) in the univariate analysis, but the impact was not significant in the multivariate analysis. The favorable outcome of DLBCL with HOTAIR high expression levels may be related to the negative correlation with c- MYC expression or c-MYC/BCL2 co-expression. CONCLUSIONS: HOTAIR expression could be one of possible mechanisms for inducing H3K27me3 via EZH2-related PRC2 activation, and induced H3K27me3 may be strongly related to aggressive DLBCLs which show poor patient outcome.