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      Long Non-Coding RNAs: Key Regulators of Epithelial-Mesenchymal Transition, Tumour Drug Resistance and Cancer Stem Cells

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          Abstract

          Epithelial mesenchymal transition (EMT), the adoption by epithelial cells of a mesenchymal-like phenotype, is a process co-opted by carcinoma cells in order to initiate invasion and metastasis. In addition, it is becoming clear that is instrumental to both the development of drug resistance by tumour cells and in the generation and maintenance of cancer stem cells. EMT is thus a pivotal process during tumour progression and poses a major barrier to the successful treatment of cancer. Non-coding RNAs (ncRNA) often utilize epigenetic programs to regulate both gene expression and chromatin structure. One type of ncRNA, called long non-coding RNAs (lncRNAs), has become increasingly recognized as being both highly dysregulated in cancer and to play a variety of different roles in tumourigenesis. Indeed, over the last few years, lncRNAs have rapidly emerged as key regulators of EMT in cancer. In this review, we discuss the lncRNAs that have been associated with the EMT process in cancer and the variety of molecular mechanisms and signalling pathways through which they regulate EMT, and finally discuss how these EMT-regulating lncRNAs impact on both anti-cancer drug resistance and the cancer stem cell phenotype.

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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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            RNA maps reveal new RNA classes and a possible function for pervasive transcription.

            Significant fractions of eukaryotic genomes give rise to RNA, much of which is unannotated and has reduced protein-coding potential. The genomic origins and the associations of human nuclear and cytosolic polyadenylated RNAs longer than 200 nucleotides (nt) and whole-cell RNAs less than 200 nt were investigated in this genome-wide study. Subcellular addresses for nucleotides present in detected RNAs were assigned, and their potential processing into short RNAs was investigated. Taken together, these observations suggest a novel role for some unannotated RNAs as primary transcripts for the production of short RNAs. Three potentially functional classes of RNAs have been identified, two of which are syntenically conserved and correlate with the expression state of protein-coding genes. These data support a highly interleaved organization of the human transcriptome.
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              Epithelial-mesenchymal transitions: twist in development and metastasis.

              Epithelial-mesenchymal transitions (EMT) are vital for morphogenesis during embryonic development and are also implicated in the conversion of early stage tumors into invasive malignancies. Several key inducers of EMT are transcription factors that repress E-cadherin expression. A recent report in Cell (Yang et al., 2004) adds Twist to this list and links EMT to the ability of breast cancer cells to enter the circulation and seed metastases.
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                Author and article information

                Contributors
                Role: Academic Editor
                Role: Academic Editor
                Journal
                Cancers (Basel)
                Cancers (Basel)
                cancers
                Cancers
                MDPI
                2072-6694
                21 April 2017
                April 2017
                : 9
                : 4
                : 38
                Affiliations
                [1 ]Thoracic Oncology Research Group, Rm 2.09, Trinity Translational Medical Institute, St. James’s Hospital, Dublin D08 W9RT, Ireland; rheery@ 123456tcd.ie
                [2 ]Masters in Translational Oncology Program, Department of Surgery, Trinity College Dublin, Trinity Translational Medical Institute, St. James’s Hospital, Dublin D08 W9RT, Ireland
                [3 ]Department of Histopathology & Morbid Anatomy, Trinity College Dublin, Dublin D08 RX0X, Ireland; Stephen.Finn@ 123456tcd.ie
                [4 ]HOPE Directorate, St. James’s Hospital, Dublin D08 RT2X, Ireland; scuffe@ 123456stjames.ie
                [5 ]Department of Clinical Medicine, School of Medicine, Trinity College Dublin, Dublin D02 R590, Ireland
                [6 ]Labmed Directorate, St. James’s Hospital, Dublin D08 K0Y5, Ireland
                Author notes
                [* ]Correspondence: sgray@ 123456stjames.ie ; Tel.: +353-1-4284945
                Article
                cancers-09-00038
                10.3390/cancers9040038
                5406713
                28430163
                1f2cf777-be09-4eb6-80d1-cdf8aad85338
                © 2017 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 27 February 2017
                : 18 April 2017
                Categories
                Review

                long non-coding rna (lncrna),epithelial-mesenchymal transition (emt),chemotherapy resistance,cancer stem cell (csc)

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