MicroRNA-214-5p involves in the protection effect of Dexmedetomidine against neurological injury in Alzheimer's disease via targeting the suppressor of zest 12.

OBJECTIVE: Alzheimer's disease (AD) is a neurological disease. Dexmedetomidine (Dex) has been evidenced to exert neuroprotective effects on multiple neurological diseases, while the function of microRNA(miR)- 214-5p on Dex-mediated AD progression via targeting the suppressor of zest 12 (SUZ12) remains unclear. This study obligates to investigate the regulatory functions of Dex, miR-214-5p and SUZ12 on AD. METHODS: The expression of miR-214-5p and SUZ12 in APPswe/PS1dE9 mice (hereinafter referred to as AD mice) was examined. Thereafter, the AD mice were treated with Dex or increased miR-214-5p or reduced SUZ12 to determine the spatial memory ability, apoptosis of hippocampal neurons and the contents of serum inflammatory and oxidative stress factors of AD mice. Finally, the target relationship between miR-214-5p and SUZ12 was detected. RESULTS: MiR-214-5p was reduced and SUZ12 was elevated in AD mice. Dex administration reduced the apoptosis of hippocampal neurons, the contents of serum inflammatory factor and oxidative stress, and attenuated the cognitive impairment of AD mice accompanied by up-regulated miR-214-5p and down-regulated SUZ12, and the overexpression of miR-214-5p or reduction of SUZ12 could effectively enhance the Dex-treated effects on AD mice. MiR-214-5p targeted SUZ12. CONCLUSION: Dex may have a potential neuroprotective effect on AD via the miR-214-5p/SUZ12 axis. This study provides novel therapeutic targets for AD treatment.

PRC2 targeting is a therapeutic strategy for EZ score defined high-risk multiple myeloma patients and overcome resistance to IMiDs.

BACKGROUND: Multiple myeloma (MM) is a malignant plasma cell disease with a poor survival, characterized by the accumulation of myeloma cells (MMCs) within the bone marrow. Epigenetic modifications in MM are associated not only with cancer development and progression, but also with drug resistance. METHODS: We identified a significant upregulation of the polycomb repressive complex 2 (PRC2) core genes in MM cells in association with proliferation. We used EPZ-6438, a specific small molecule inhibitor of EZH2 methyltransferase activity, to evaluate its effects on MM cells phenotype and gene expression prolile. RESULTS: PRC2 targeting results in growth inhibition due to cell cycle arrest and apoptosis together with polycomb, DNA methylation, TP53, and RB1 target genes induction. Resistance to EZH2 inhibitor is mediated by DNA methylation of PRC2 target genes. We also demonstrate a synergistic effect of EPZ-6438 and lenalidomide, a conventional drug used for MM treatment, activating B cell transcription factors and tumor suppressor gene expression in concert with MYC repression. We establish a gene expression-based EZ score allowing to identify poor prognosis patients that could benefit from EZH2 inhibitor treatment. CONCLUSIONS: These data suggest that PRC2 targeting in association with IMiDs could have a therapeutic interest in MM patients characterized by high EZ score values, reactivating B cell transcription factors, and tumor suppressor genes.

Structure, mechanism, and regulation of polycomb-repressive complex 2.

Polycomb repressive complex 2 (PRC2) methylates lysine 27 in histone H3, a modification associated with epigenetic gene silencing. This complex plays a fundamental role in regulating cellular differentiation and development, and PRC2 overexpression and mutations have been implicated in numerous cancers. In this Minireview, we examine recent studies elucidating the first crystal structures of the PRC2 core complex, yielding seminal insights into its catalytic mechanism, substrate specificity, allosteric regulation, and inhibition by a class of small molecules that are currently undergoing cancer clinical trials. We conclude by exploring unresolved questions and future directions for inquiry regarding PRC2 structure and function.

Therapeutic targeting of polycomb and BET bromodomain proteins in diffuse intrinsic pontine gliomas.

Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive pediatric brainstem tumor characterized by rapid and uniform patient demise. A heterozygous point mutation of histone H3 occurs in more than 80% of these tumors and results in a lysine-to-methionine substitution (H3K27M). Expression of this histone mutant is accompanied by a reduction in the levels of polycomb repressive complex 2 (PRC2)-mediated H3K27 trimethylation (H3K27me3), and this is hypothesized to be a driving event of DIPG oncogenesis. Despite a major loss of H3K27me3, PRC2 activity is still detected in DIPG cells positive for H3K27M. To investigate the functional roles of H3K27M and PRC2 in DIPG pathogenesis, we profiled the epigenome of H3K27M-mutant DIPG cells and found that H3K27M associates with increased H3K27 acetylation (H3K27ac). In accordance with previous biochemical data, the majority of the heterotypic H3K27M-K27ac nucleosomes colocalize with bromodomain proteins at the loci of actively transcribed genes, whereas PRC2 is excluded from these regions; this suggests that H3K27M does not sequester PRC2 on chromatin. Residual PRC2 activity is required to maintain DIPG proliferative potential, by repressing neuronal differentiation and function. Finally, to examine the therapeutic potential of blocking the recruitment of bromodomain proteins by heterotypic H3K27M-K27ac nucleosomes in DIPG cells, we performed treatments in vivo with BET bromodomain inhibitors and demonstrate that they efficiently inhibit tumor progression, thus identifying this class of compounds as potential therapeutics in DIPG.

Enhancer of zeste homolog 2 (EZH2) promotes tumour cell migration and invasion via epigenetic repression of E-cadherin in renal cell carcinoma.

OBJECTIVE: To investigate the molecular mechanism and clinical significance for an oncogenic role of enhancer of zeste homolog 2 (EZH2) in renal cell carcinoma (RCC). MATERIALS AND METHODS: Immunohistochemistry analyses of EZH2, histone H3 trimethyl Lys27 (H3K27me3) and E-cadherin were performed in tumour tissue samples from 257 patients with RCC. Regulatory effects of EZH2 on E-cadherin expression were examined by quantitative real-time polymerase chain reaction, Western blot, chromatin immunoprecipitation assay and immunohistochemical staining. Migration and invasion assays were performed in RCC cell lines. Tumour xenograft experiments with RCC cells were carried out in nude mice. RESULTS: EZH2 promoted migration and invasion in RCC cell lines. Silencing EZH2 with short-hairpin EZH2 (shEZH2) or 3-deazaneplanocin A (DZNep) inhibited migration and invasion (P < 0.001), up-regulated the expression of E-cadherin in vitro, inhibited tumour growth, and prolonged survival in vivo (P = 0.022). EZH2 expression accompanied with E-cadherin repression was associated with advanced disease stage (P = 0.004) and poor overall (P < 0.001) and disease-free survival (P < 0.001). CONCLUSION: EZH2 may contribute to RCC progression and is a potential therapeutic target for advanced RCC.

Characterization and pharmacologic targeting of EZH2, a fetal retinal protein and epigenetic regulator, in human retinoblastoma.

Retinoblastoma (RB) is the most common primary intraocular cancer in children, and the third most common cancer overall in infants. No molecular-targeted therapy for this lethal tumor exists. Since the tumor suppressor RB1, whose genetic inactivation underlies RB, is upstream of the epigenetic regulator EZH2, a pharmacologic target for many solid tumors, we reasoned that EZH2 might regulate human RB tumorigenesis. Histologic and immunohistochemical analyses were performed using an EZH2 antibody in sections from 43 samples of primary, formalin-fixed, paraffin-embedded human RB tissue, cryopreserved mouse retina, and in whole cell lysates from human RB cell lines (Y79 and WERI-Rb1), primary human fetal retinal pigment epithelium (RPE) and fetal and adult retina, mouse retina and embryonic stem (ES) cells. Although enriched during fetal human retinal development, EZH2 protein was not present in the normal postnatal retina. However, EZH2 was detected in all 43 analyzed human RB specimens, indicating that EZH2 is a fetal protein expressed in postnatal human RB. EZH2 expression marked single RB cell invasion into the optic nerve, a site of invasion whose involvement may influence the decision for systemic chemotherapy. To assess the role of EZH2 in RB cell survival, human RB and primary RPE cells were treated with two EZH2 inhibitors (EZH2i), GSK126 and SAH-EZH2 (SAH). EZH2i impaired intracellular adenosine triphosphate (ATP) production, an indicator of cell viability, in a time and dose-dependent manner, but did not affect primary human fetal RPE. Thus, aberrant expression of a histone methyltransferase protein is a feature of human RB. This is the first time this mechanism has been implicated for an eye, adnexal, or orbital tumor. The specificity of EZH2i toward human RB cells, but not RPE, warrants further in vivo testing in animal models of RB, especially those EZH2i currently in clinical trials for solid tumors and lymphoma.

Ribavirin as a tri-targeted antitumor repositioned drug.

The aim of the present study was to demonstrate that ribavirin, a known inhibitor of eIF4E and inosine 5'-phosphate dehydrogenase (IMPDH), also inhibits histone methyltransferase zeste homolog 2 (EZH2). A computational searching revealed that ribavirin has a high structural similarity to 3-deazaneplanocin A (DZNep). The growth inhibitory effects of ribavirin as well as its effects upon epigenetic enzymes were evaluated in various cancer cell lines. siRNA assays were used to downregulate eIF4E, EZH2 and IMPDH to determine the contribution of these targets to the growth inhibitory effects of ribavirin. Ribavirin decreased EZH2 expression, inhibited histone methyltransferase activity and decreased H3K27 trimethylation. Ribavirin induced variable growth inhibition in a number of cell lines and downregulation of the targets, EZH2, eIF4E and IMPDH1 and 2 by siRNA led to comparable growth inhibition while no significant further reduction in viability was observed when siRNA transfected cells were treated with ribavirin. The results showed that ribavirin inhibits these cancer targets and should thus be studied for cancer therapy.

Inhibition of EZH2 expression is associated with the proliferation, apoptosis, and migration of SW620 colorectal cancer cells in vitro.

Epigenetic changes have been recently recognized as important in many human cancers. Enhancer of zeste homologue 2 (EZH2)gene has shown overexpression in various human cancers, consistent with a straightforward role of EZH2 as an oncogene, but its function in carcinogenesis is partly contradictory. The role of EZH2 in development of human colorectal cancer (CRC) has not yet been clarified. In present study, we observed up-regulation of EZH2 expression in tumor tissues from CRC patients [corrected]. The expression of EZH2 in CRC cell lines is consistent with the trend in cancer tissues using RT-PCR. We showed that TNM stage and lymph node metastasis in CRC patients are significantly correlated with EZH2 expression levels [corrected]. EZH2 level of transcription and protein was inhibited by small interfering RNA (siRNA). More importantly, EZH2-siRNA inhibited the proliferation and migration of SW620 cells while promoting their apoptosis, and inducing G0/G1 cell cycle arrest of CRC cells. Collectively, our results suggest that upregulated EZH2 expression may contribute to the progression of the patients with CRC. A comprehensive study of epigenetic mechanisms and the relevance of EZH2 in CRC is important for fully understanding this disease and as a basis for developing new treatment options in patients with CRC [corrected].