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      OncoTargets and Therapy (submit here)

      This international, peer-reviewed Open Access journal by Dove Medical Press focuses on the pathological basis of cancers, potential targets for therapy and treatment protocols to improve the management of cancer patients. Publishing high-quality, original research on molecular aspects of cancer, including the molecular diagnosis, since 2008. Sign up for email alerts here. 50,877 Monthly downloads/views I 4.345 Impact Factor I 7.0 CiteScore I 0.81 Source Normalized Impact per Paper (SNIP) I 0.811 Scimago Journal & Country Rank (SJR)

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      MiR-101-3p and Syn-Cal14.1a Synergy in Suppressing EZH2-Induced Progression of Breast Cancer

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          Abstract

          Objective

          EZH2 is the catalytic subunit of the polycomb repressive complex 2 (PRC2) and has been documented as an oncogene in breast cancer. The microRNA (miR)-101-3p can suppress breast cancer progression by targeting with EZH2. Syn-cal14.1a, a synthetic peptide derived from Californiconus californicus (Cal14.1a), can decrease the cell viability and activate the cell apoptosis in cancer. In this study, we explored whether the synergy of miR-101-3p mimic and syn-cal14.1a could inhibit the expression of EZH2. We also investigated this binding treatment’s effects on the suppression of breast cancer cells.

          Methods

          MiR-101-3p mimic was transfected and syn-cal14.1a was added in SK-BR-3 and MCF-7 breast cancer cells. The expression of EZH2 protein level was determined. Then, cell proliferation, migration, invasion, and apoptosis were observed.

          Results

          MiR-101-3p and syn-cal14.1a, when applied together, exerted a synergistic anti-EZH2 expression in breast cancer cells. The combination of miR-101-3p and syn-cal14.1a synergistically suppressed the EZH2-induced breast cancer cell migration, invasion, and proliferation. In parallel, this synergy treatment was able to promote the apoptosis of breast cancer cells. To our knowledge, this is the first report describing inhibition of EZH2 in human breast cancer cell lines by syn-cal14.1a.

          Conclusion

          The anti-EZH2 roles of miR-101-3p and/or syn-cal14.1a could provide an effective therapeutic strategy in breast cancer. These data provide significant insights into molecular mechanisms of breast cancer and may have benefits in clinical therapeutics for breast cancer.

          Most cited references24

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          Genomic loss of microRNA-101 leads to overexpression of histone methyltransferase EZH2 in cancer.

          Enhancer of zeste homolog 2 (EZH2) is a mammalian histone methyltransferase that contributes to the epigenetic silencing of target genes and regulates the survival and metastasis of cancer cells. EZH2 is overexpressed in aggressive solid tumors by mechanisms that remain unclear. Here we show that the expression and function of EZH2 in cancer cell lines are inhibited by microRNA-101 (miR-101). Analysis of human prostate tumors revealed that miR-101 expression decreases during cancer progression, paralleling an increase in EZH2 expression. One or both of the two genomic loci encoding miR-101 were somatically lost in 37.5% of clinically localized prostate cancer cells (6 of 16) and 66.7% of metastatic disease cells (22 of 33). We propose that the genomic loss of miR-101 in cancer leads to overexpression of EZH2 and concomitant dysregulation of epigenetic pathways, resulting in cancer progression.
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            Death receptor-induced cell killing.

            Apoptosis pathways activated by death receptors of the tumour necrosis factor (TNF) family such as Fas, TNFR1, or the TRAIL receptors DR4 and DR5 are implicated in diverse diseases. These are also the best-understood apoptosis pathways and many of our ideas about apoptosis regulation come from studying these pathways. Cell killing from such receptors occurs because of recruitment to the receptor of the adaptor protein FADD, which in turn recruits the pro form of caspase-8. Aggregation of pro-caspase-8 leads to its auto-activation and subsequent activation of effector caspases such as caspase-3. The apoptotic signal can be amplified through the mitochondria and inhibited through the action of competing molecules such as the inhibitor c-FLIP, which binds to the receptor complex in place of caspase-8. This simple mechanism explains much of the cell death that is induced by death receptors. However, recent studies indicate that we must incorporate new information into this model. Some examples that add new layers of complexity will be discussed in this review.
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              Enhancer of zeste homolog 2 epigenetically silences multiple tumor suppressor microRNAs to promote liver cancer metastasis.

              Epigenetic alterations and microRNA (miRNA) deregulation are common in hepatocellular carcinoma (HCC). The histone H3 lysine 27 (H3K27) tri-methylating enzyme, enhancer of zeste homolog 2 (EZH2) mediates epigenetic silencing of gene expression and is frequently up-regulated in human cancers. In this study we aimed to delineate the implications of EZH2 up-regulation in miRNA deregulation and HCC metastasis. Expressions of a total of 90 epigenetic regulators were first determined in 38 pairs of primary HCCs and their corresponding nontumorous livers. We identified EZH2 and its associated polycomb repressive complex 2 (PRC2) as one of the most significantly deregulated epigenetic regulators in primary HCC samples. Up-regulation of EZH2 was next confirmed in 69.5% (41/59) of primary HCCs. Clinicopathologically, EZH2 up-regulation was associated with HCC progression and multiple HCC metastatic features, including venous invasion (P = 0.043), direct liver invasion (P = 0.014), and absence of tumor encapsulation (P = 0.043). We further demonstrated that knockdown of EZH2 in HCC cell lines reduced the global levels of tri-methylated H3K27, and suppressed HCC motility in vitro and pulmonary metastasis in a nude mouse model. By interrogating the miRNA expression profile in EZH2-knockdown cell lines and primary HCC samples, we identified a subset of miRNA that was epigenetically suppressed by EZH2 in human HCC. These included well-characterized tumor-suppressor miRNAs, such as miR-139-5p, miR-125b, miR-101, let-7c, and miR-200b. Pathway enrichment analysis revealed a common regulatory role of these EZH2-silenced miRNAs in modulating cell motility and metastasis-related pathways. Our findings suggest that EZH2 exerts its prometastatic function by way of epigenetic silencing of multiple tumor suppressor miRNAs. Our study demonstrated that EZH2 epigenetically silenced multiple miRNAs that negatively regulate HCC metastasis. Copyright © 2012 American Association for the Study of Liver Diseases.
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                Author and article information

                Journal
                Onco Targets Ther
                ott
                ott
                OncoTargets and therapy
                Dove
                1178-6930
                28 September 2020
                2020
                : 13
                : 9599-9609
                Affiliations
                [1 ]Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine , Shanghai, People’s Republic of China
                [2 ]Assisted Reproduction Technology Center, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine , Shanghai, People’s Republic of China
                [3 ]Department of Plastic Surgery, Zhongshan Hospital of Xiamen University , Xiamen, Fujian, People’s Republic of China
                [4 ]Urologic Medical Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai, People’s Republic of China
                [5 ]Department of Health Medicine, Zhongshan Hospital of Xiamen University , Xiamen, Fujian, People’s Republic of China
                [6 ]Department of Gastrointestinal Surgery, Institute of Gastrointestinal Oncology, Zhongshan Hospital of Xiamen University , Xiamen, Fujian, People’s Republic of China
                Author notes
                Correspondence: Jingjing Hou; Yongsheng Yu Email jjhou@xmu.edu.cn; yongshengyu@tongji.edu.cn
                [*]

                These authors contributed equally to this work

                Article
                264600
                10.2147/OTT.S264600
                7532305
                33061442
                0868dd7f-0c96-45e6-a5e6-ed0b7fd93f44
                © 2020 Jiang et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                History
                : 05 June 2020
                : 03 August 2020
                Page count
                Figures: 7, References: 37, Pages: 11
                Funding
                Funded by: National Natural Science Foundation of China, open-funder-registry 10.13039/501100001809;
                Funded by: the Shanghai Pujiang Program;
                Funded by: Scientific Research Foundation of Shanghai Municipal Commission of Health and Family Planning;
                This research was funded by the National Natural Science Foundation of China (81902622 and 81902996), the Shanghai Pujiang Program (18PJ1409400), the Shanghai “Science and Technology Innovation Action Plan“ Hong Kong, Macao, and Taiwan Science and Technology Cooperation Project (20430760100), and the Scientific Research Foundation of Shanghai Municipal Commission of Health and Family Planning (20174Y0218). We thank Dr. Yanchun Meng from Shanghai Cancer Center of Fudan University for her assitance.
                Categories
                Original Research

                Oncology & Radiotherapy
                breast cancer,mir-101-3p,conotoxins,synthetic peptide,ezh2,synergism
                Oncology & Radiotherapy
                breast cancer, mir-101-3p, conotoxins, synthetic peptide, ezh2, synergism

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