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      Exploring the mechanisms behind long noncoding RNAs and cancer

      review-article
      a , b , c , a , b , c ,
      Non-coding RNA Research
      KeAi Publishing
      lncRNA, Cancer, Chromatin, HOTAIR, TUG1, MEG3

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          Abstract

          Over the past decade, long noncoding RNAs (lncRNAs) have been identified as significant players in gene regulation. They are often differentially expressed and widely-associated with a majority of cancer types. The aberrant expression of these transcripts has been linked to tumorigenesis, metastasis, cancer stage progression and patient survival. Despite their apparent link to cancer, it has been challenging to gain a mechanistic understanding of how they contribute to cancer, partially due the difficulty in discriminating functional RNAs from other noncoding transcription events. However, there are several well-studied lncRNAs where specific mechanisms have been more clearly defined, leading to new discoveries into how these RNAs function. One major observation that has come to light is the context-dependence of lncRNA mechanisms, where they often have unique function in specific cell types and environment. Here, we review the molecular mechanisms of lncRNAs with a focus on cancer pathways, illustrating a few informative examples. Together, this type of detailed insight will lead to a greater understanding of the potential for the application of lncRNAs as targets of cancer therapies and diagnostics.

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          Most cited references61

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          Long noncoding RNA as modular scaffold of histone modification complexes.

          Long intergenic noncoding RNAs (lincRNAs) regulate chromatin states and epigenetic inheritance. Here, we show that the lincRNA HOTAIR serves as a scaffold for at least two distinct histone modification complexes. A 5' domain of HOTAIR binds polycomb repressive complex 2 (PRC2), whereas a 3' domain of HOTAIR binds the LSD1/CoREST/REST complex. The ability to tether two distinct complexes enables RNA-mediated assembly of PRC2 and LSD1 and coordinates targeting of PRC2 and LSD1 to chromatin for coupled histone H3 lysine 27 methylation and lysine 4 demethylation. Our results suggest that lincRNAs may serve as scaffolds by providing binding surfaces to assemble select histone modification enzymes, thereby specifying the pattern of histone modifications on target genes.
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            Molecular interplay of the noncoding RNA ANRIL and methylated histone H3 lysine 27 by polycomb CBX7 in transcriptional silencing of INK4a.

            Expression of the INK4b/ARF/INK4a tumor suppressor locus in normal and cancerous cell growth is controlled by methylation of histone H3 at lysine 27 (H3K27me) as directed by the Polycomb group proteins. The antisense noncoding RNA ANRIL of the INK4b/ARF/INK4a locus is also important for expression of the protein-coding genes in cis, but its mechanism has remained elusive. Here we report that chromobox 7 (CBX7) within the polycomb repressive complex 1 binds to ANRIL, and both CBX7 and ANRIL are found at elevated levels in prostate cancer tissues. In concert with H3K27me recognition, binding to RNA contributes to CBX7 function, and disruption of either interaction impacts the ability of CBX7 to repress the INK4b/ARF/INK4a locus and control senescence. Structure-guided analysis reveals the molecular interplay between noncoding RNA and H3K27me as mediated by the conserved chromodomain. Our study suggests a mechanism by which noncoding RNA participates directly in epigenetic transcriptional repression. Copyright (c) 2010 Elsevier Inc. All rights reserved.
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              Kcnq1ot1 antisense noncoding RNA mediates lineage-specific transcriptional silencing through chromatin-level regulation.

              Recent investigations have implicated long antisense noncoding RNAs in the epigenetic regulation of chromosomal domains. Here we show that Kcnq1ot1 is an RNA polymerase II-encoded, 91 kb-long, moderately stable nuclear transcript and that its stability is important for bidirectional silencing of genes in the Kcnq1 domain. Kcnq1ot1 interacts with chromatin and with the H3K9- and H3K27-specific histone methyltransferases G9a and the PRC2 complex in a lineage-specific manner. This interaction correlates with the presence of extended regions of chromatin enriched with H3K9me3 and H3K27me3 in the Kcnq1 domain in placenta, whereas fetal liver lacks both chromatin interactions and heterochromatin structures. In addition, the Kcnq1 domain is more often found in contact with the nucleolar compartment in placenta than in liver. Taken together, our data describe a mechanism whereby Kcnq1ot1 establishes lineage-specific transcriptional silencing patterns through recruitment of chromatin remodeling complexes and maintenance of these patterns through subsequent cell divisions occurs via targeting the associated regions to the perinucleolar compartment.
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                Author and article information

                Contributors
                Journal
                Noncoding RNA Res
                Noncoding RNA Res
                Non-coding RNA Research
                KeAi Publishing
                2468-0540
                31 March 2018
                September 2018
                31 March 2018
                : 3
                : 3
                : 108-117
                Affiliations
                [a ]Molecular Biology Program, University of Colorado Denver Anschutz Medical Campus 12801 East 17th Ave., Aurora, CO, United States
                [b ]Department of Biochemistry and Molecular Genetics, University of Colorado Denver Anschutz Medical Campus 12801 East 17th Ave., Aurora, CO, United States
                [c ]RNA Bioscience Initiative, University of Colorado Denver Anschutz Medical Campus 12801 East 17th Ave., Aurora, CO, United States
                Author notes
                []Corresponding author. Department of Biochemistry and Molecular Genetics, University of Colorado Denver Anschutz Medical Campus 12801 East 17th Ave., Aurora, CO, United States. aaron.m.johnson@ 123456ucdenver.edu
                Article
                S2468-0540(17)30052-5
                10.1016/j.ncrna.2018.03.001
                6114262
                30175284
                c7e495a8-3dd4-4839-ba6a-2e96c26eb306
                © 2018 Production and hosting by Elsevier B.V. on behalf of KeAi Communications Co., Ltd.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 23 March 2018
                : 23 March 2018
                Categories
                Article

                lncrna,cancer,chromatin,hotair,tug1,meg3
                lncrna, cancer, chromatin, hotair, tug1, meg3

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