MicroRNAs (miRNAs) are endogenous ∼23 nt RNAs that play important gene-regulatory roles in animals and plants by pairing to the mRNAs of protein-coding genes to direct their posttranscriptional repression. This review outlines the current understanding of miRNA target recognition in animals and discusses the widespread impact of miRNAs on both the expression and evolution of protein-coding genes.

MicroRNAs: Target Recognition and Regulatory Functions

The term epigenetics is defined as heritable changes in gene expression that are not due to alterations of the DNA sequence. In the last years, it has become more and more evident that dysregulated epigenetic regulatory processes have a central role in cancer onset and progression. In contrast to DNA mutations, epigenetic modifications are reversible and, hence, suitable for pharmacological interventions. Reversible histone methylation is an important process within epigenetic regulation, and the investigation of its role in cancer has led to the identification of lysine methyltransferases and demethylases as promising targets for new anticancer drugs. In this review, we describe those enzymes and their inhibitors that have already reached the first stages of clinical trials in cancer therapy, namely the histone methyltransferases DOT1L and EZH2 as well as the demethylase LSD1.

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Targeting histone methyltransferases and demethylases in clinical trials for cancer therapy

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.

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Regulation and Role of EZH2 in Cancer

Gastric cancer is the fourth most common malignancy and the third leading cause of cancer-related deaths worldwide. Advanced gastric cancer patients can notably benefit from chemotherapy including adriamycin, platinum drugs, 5-fluorouracil, vincristine, and paclitaxel as well as targeted therapy drugs. Nevertheless, primary drug resistance or acquisition drug resistance eventually lead to treatment failure and poor outcomes of the gastric cancer patients. The detailed mechanisms involved in gastric cancer drug resistance have been revealed. Interestingly, different noncoding RNAs (ncRNAs), such as microRNAs (miRNAs), long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs), are critically involved in gastric cancer development. Multiple lines of evidences demonstrated that ncRNAs play a vital role in gastric cancer resistance to chemotherapy reagents and targeted therapy drugs. In this review, we systematically summarized the emerging role and detailed molecular mechanisms of ncRNAs impact drug resistance of gastric cancer. Additionally, we propose the potential clinical implications of ncRNAs as novel therapeutic targets and prognostic biomarkers for gastric cancer.

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Noncoding RNAs in gastric cancer: implications for drug resistance

Enhancer of zeste homolog 2 (EZH2) is the catalytic subunit of the polycomb repressive complex 2 and suppresses gene expression by catalyzing histone H3 methylation on lysine 27. EZH2 is overexpressed in metastatic prostate cancer and has been shown to promote cell proliferation and metastasis. Here we show that EZH2 also suppresses prostate cancer apoptosis by coordinating the epigenetic silencing of two proapoptotic microRNAs (miRNA), miR-205 and miR-31. We previously reported that miR-205 promotes apoptosis by targeting antiapoptotic protein Bcl-w and miR-205 is silenced in prostate cancer through promoter methylation. In this study, we found that EZH2 suppresses miR-31 expression by trimethylation of lysine 27 on histone 3 on the miR-31 promoter. SiRNA knockdown of EZH2 increased miR-31 expression and decreased the antiapoptotic protein E2F6 (E2F transcription factor 6) (a target of miR-31), resulting in the sensitization of prostate cancer cells to docetaxel-induced apoptosis. Conversely, overexpression of EZH2 blocked docetaxel-induced apoptosis. We further demonstrated that miR-205 silencing is linked to miR-31 silencing through EZH2. Suppression of miR-205 with an miRNA inhibitor caused an increase of EZH2 protein, which in turn inhibited miR-31 expression. Conversely, overexpression of miR-205 decreased EZH2 protein and increased miR-31 expression. In paired human prostate cancer specimens and adjacent normal tissues, we observed that the decrease of miR-205 expression correlated with EZH2 overexpression and miR-31 silencing. Thus, EZH2 integrates the epigenetic silencing of miR-205 and miR-31 to confer resistance to chemotherapy-induced apoptosis.

Polycomb protein EZH2 suppresses apoptosis by silencing the proapoptotic miR-31

MicroRNA-124 (miR-124), a pivotal member of the p53 network, was found to be down-regulated in multiple types of tumors and further reported as tumor suppressor microRNA In this study, we found that miR-124 was down-regulated in gastric cancer cell lines and specimens Restoration of miR-124 expression inhibited the proliferation and colony formation of gastric cancer cells EZH2 (enhancer of zeste homolog 2), which has been shown to be an important transcription factor involved in the proliferation and metastasis of tumor cells, was here confirmed to be a direct target gene of miR-124 On the other hand, silencing EZH2 also inhibits cell proliferation of gastric cancer cells Furthermore, the treatment combining miR-124 with 5-fluorouracil (5-FU) significantly showed more efficient anti-tumor effects than single treatment of miR-124 or 5-FU, and over-expression of miR-124 suppresses the tumor growth in vivo Our study indicate that miR-124 can suppress gastric cancer cell growth by directly targeting the EZH2 gene and sensitize the treatment effect of 5-FU Therefore, miR-124 shows tumor-suppressive activity and may be a new and useful approach of gastric cancer therapy

microRNA-124 inhibits proliferation and induces apoptosis by directly repressing EZH2 in gastric cancer

Introduction
Nasopharyngeal carcinoma (NPC) is a common malignant tumor of the head and neck. The STGC3 gene is related to development of nasopharyngeal cancer. The aim of this study is to explore the promoter region of the STGC3 gene.

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Identification and analysis of the promoter region of the STGC3 gene.

The aim of this study was to analyze the functional sites of the nasopharyngeal candidate tumour suppressor gene STGC3. Recombinant plasmid pcDNA3.1TM/myc-His B-STGC3 was constructed. Site-directed mutagenesis of pcDNA3.1TM/myc-His B-STGC3 plasmid at sites of C656G, C725T and T913G was induced by the Stratagene mutagenesis method. Recombinant plasmids with point mutations at C656G, C725T and T913G of gene STGC3 were named as STGC3-C656G, STGC3-C725T and STGC3-T913G, respectively. CNE2 cell lines stably expressing wild and mutant STGC3 genes were established. STGC3 expression was detected by Western Blotting and immunocytochemistry. Cell proliferation was analyzed by 3-(4, 5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and trypan blue staining. Flow cytometry analysis was used to assess apoptosis of CNE2 cells. Bax protein expression was detected by Western Blotting.

Proteins of wild-type and mutant STGC3 genes were expressed in the cytoplasm and nucleus of CNE2 cells. Compared with the control groups, in cells stably expressing wild-type STGC3 and STGC3-T913G genes, cell proliferation was significantly inhibited, whereas levels of apoptosis and Bax protein expression were significantly increased. However, the cell proliferation, apoptosis and Bax protein expression in cells stably expressing STGC3-C656G and STGC3-C725T genes were not significantly different from those in the control groups. Our results suggest that mutations at 656C and 725C, but not 913T, abolished the effects of the wild-type STGC3 gene on CNE2 cells and that the 656C and 725C were important sites in gene STGC3 for its negative regulation on cell growth.

Suyun Li

Papers

microRNA-124 inhibits proliferation and induces apoptosis by directly repressing EZH2 in gastric cancer

Identification and analysis of the promoter region of the STGC3 gene.

The 656C and 725C are two important sites in gene STGC3 for its negative regulation on cell growth