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      miR-29s: a family of epi-miRNAs with therapeutic implications in hematologic malignancies

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          Abstract

          A wealth of studies has highlighted the biological complexity of hematologic malignancies and the role of dysregulated signal transduction pathways. Along with the crucial role of genetic abnormalities, epigenetic aberrations are nowadays emerging as relevant players in cancer development, and significant research efforts are currently focusing on mechanisms by which histone post-translational modifications, DNA methylation and noncoding RNAs contribute to the pathobiology of cancer. As a consequence, these studies have provided the rationale for the development of epigenetic drugs, such as histone deacetylase inhibitors and demethylating compounds, some of which are currently in advanced phase of pre-clinical investigation or in clinical trials. In addition, a more recent body of evidence indicates that microRNAs (miRNAs) might target effectors of the epigenetic machinery, which are aberrantly expressed or active in cancers, thus reverting those epigenetic abnormalities driving tumor initiation and progression. This review will focus on the broad epigenetic activity triggered by members of the miR-29 family, which underlines the potential of miR-29s as candidate epi-therapeutics for the treatment of hematologic malignancies.

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          Most cited references175

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          Roles for microRNAs in conferring robustness to biological processes.

          Biological systems use a variety of mechanisms to maintain their functions in the face of environmental and genetic perturbations. Increasing evidence suggests that, among their roles as posttranscriptional repressors of gene expression, microRNAs (miRNAs) help to confer robustness to biological processes by reinforcing transcriptional programs and attenuating aberrant transcripts, and they may in some network contexts help suppress random fluctuations in transcript copy number. These activities have important consequences for normal development and physiology, disease, and evolution. Here, we will discuss examples and principles of miRNAs that contribute to robustness in animal systems. Copyright © 2012 Elsevier Inc. All rights reserved.
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            The DNA methyltransferases of mammals.

            T Bestor (2000)
            The biological significance of 5-methylcytosine was in doubt for many years, but is no longer. Through targeted mutagenesis in mice it has been learnt that every protein shown by biochemical tests to be involved in the establishment, maintenance or interpretation of genomic methylation patterns is encoded by an essential gene. A human genetic disorder (ICF syndrome) has recently been shown to be caused by mutations in the DNA methyltransferase 3B (DNMT3B) gene. A second human disorder (Rett syndrome) has been found to result from mutations in the MECP2 gene, which encodes a protein that binds to methylated DNA. Global genome demethylation caused by targeted mutations in the DNA methyltransferase-1 (Dnmt1) gene has shown that cytosine methylation plays essential roles in X-inactivation, genomic imprinting and genome stabilization. The majority of genomic 5-methylcytosine is now known to enforce the transcriptional silence of the enormous burden of transposons and retroviruses that have accumulated in the mammalian genome. It has also become clear that programmed changes in methylation patterns are less important in the regulation of mammalian development than was previously believed. Although a number of outstanding questions have yet to be answered (one of these questions involves the nature of the cues that designate sites for methylation at particular stages of gametogenesis and early development), studies of DNA methyltransferases are likely to provide further insights into the biological functions of genomic methylation patterns.
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              Widespread microRNA repression by Myc contributes to tumorigenesis.

              The c-Myc oncogenic transcription factor (Myc) is pathologically activated in many human malignancies. Myc is known to directly upregulate a pro-tumorigenic group of microRNAs (miRNAs) known as the miR-17-92 cluster. Through the analysis of human and mouse models of B cell lymphoma, we show here that Myc regulates a much broader set of miRNAs than previously anticipated. Unexpectedly, the predominant consequence of activation of Myc is widespread repression of miRNA expression. Chromatin immunoprecipitation reveals that much of this repression is likely to be a direct result of Myc binding to miRNA promoters. We further show that enforced expression of repressed miRNAs diminishes the tumorigenic potential of lymphoma cells. These results demonstrate that extensive reprogramming of the miRNA transcriptome by Myc contributes to tumorigenesis.
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                Author and article information

                Journal
                Oncotarget
                Oncotarget
                ImpactJ
                Oncotarget
                Impact Journals LLC
                1949-2553
                30 May 2015
                12 April 2015
                : 6
                : 15
                : 12837-12861
                Affiliations
                1 Department of Experimental and Clinical Medicine, Magna Graecia University and Medical Oncology Unit, T. Campanella Cancer Center, Salvatore Venuta University Campus, Catanzaro, Italy
                2 Laboratory of Tissue Engineering-Innovative Technology Platforms for Tissue Engineering (PON01-00829), Rizzoli Orthopedic Institute, Palermo, Italy
                3 Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA, USA
                Author notes
                Correspondence to: Pierfrancesco Tassone, tassone@ 123456unicz.it
                Article
                10.18632/oncotarget.3805
                4536984
                25968566
                0b42d315-f580-4baf-914a-4fead5a31020
                Copyright: © 2015 Amodio et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 15 February 2015
                : 18 March 2015
                Categories
                Review

                Oncology & Radiotherapy
                mir-29a,mir-29b,mir-29c,hematologic malignancies,multiple myeloma
                Oncology & Radiotherapy
                mir-29a, mir-29b, mir-29c, hematologic malignancies, multiple myeloma

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