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      Integrative analyses reveal a long noncoding RNA-mediated sponge regulatory network in prostate cancer

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          Abstract

          Mounting evidence suggests that long noncoding RNAs (lncRNAs) can function as microRNA sponges and compete for microRNA binding to protein-coding transcripts. However, the prevalence, functional significance and targets of lncRNA-mediated sponge regulation of cancer are mostly unknown. Here we identify a lncRNA-mediated sponge regulatory network that affects the expression of many protein-coding prostate cancer driver genes, by integrating analysis of sequence features and gene expression profiles of both lncRNAs and protein-coding genes in tumours. We confirm the tumour-suppressive function of two lncRNAs (TUG1 and CTB-89H12.4) and their regulation of PTEN expression in prostate cancer. Surprisingly, one of the two lncRNAs, TUG1, was previously known for its function in polycomb repressive complex 2 (PRC2)-mediated transcriptional regulation, suggesting its sub-cellular localization-dependent function. Our findings not only suggest an important role of lncRNA-mediated sponge regulation in cancer, but also underscore the critical influence of cytoplasmic localization on the efficacy of a sponge lncRNA.

          Abstract

          Long non-coding RNAs (lncRNA; >200 base pair nucleic acids with little protein-coding capacity) are emerging as potentially important regulators of oncogenesis. Here the authors show tumour suppressive lncRNA sponge function for the protein products of prostate cancer driver genes.

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          A coding-independent function of gene and pseudogene mRNAs regulates tumour biology

          Laura Poliseno, Leonardo Salmena, JiangWen Zhang … (2010)
          The canonical role of messenger RNA (mRNA) is to deliver protein-coding information to sites of protein synthesis. However, given that microRNAs bind to RNAs, we hypothesized that RNAs possess a biological role in cancer cells that relies upon their ability to compete for microRNA binding and is independent of their protein-coding function. As a paradigm for the protein-coding-independent role of RNAs, we describe the functional relationship between the mRNAs produced by the PTEN tumour suppressor gene and its pseudogene (PTENP1) and the critical consequences of this interaction. We find that PTENP1 is biologically active as determined by its ability to regulate cellular levels of PTEN, and that it can exert a growth-suppressive role. We also show that PTENP1 locus is selectively lost in human cancer. We extend our analysis to other cancer-related genes that possess pseudogenes, such as oncogenic KRAS. Further, we demonstrate that the transcripts of protein coding genes such as PTEN are also biologically active. Together, these findings attribute a novel biological role to expressed pseudogenes, as they can regulate coding gene expression, and reveal a non-coding function for mRNAs.
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            Ensembl 2012

            Paul Flicek, M. Amode, Daniel Barrell … (2011)
            The Ensembl project (http://www.ensembl.org) provides genome resources for chordate genomes with a particular focus on human genome data as well as data for key model organisms such as mouse, rat and zebrafish. Five additional species were added in the last year including gibbon (Nomascus leucogenys) and Tasmanian devil (Sarcophilus harrisii) bringing the total number of supported species to 61 as of Ensembl release 64 (September 2011). Of these, 55 species appear on the main Ensembl website and six species are provided on the Ensembl preview site (Pre!Ensembl; http://pre.ensembl.org) with preliminary support. The past year has also seen improvements across the project.
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              Coding-independent regulation of the tumor suppressor PTEN by competing endogenous mRNAs.

              Yvonne Tay, Lev Kats, Leonardo Salmena … (2011)
              Here, we demonstrate that protein-coding RNA transcripts can crosstalk by competing for common microRNAs, with microRNA response elements as the foundation of this interaction. We have termed such RNA transcripts as competing endogenous RNAs (ceRNAs). We tested this hypothesis in the context of PTEN, a key tumor suppressor whose abundance determines critical outcomes in tumorigenesis. By a combined computational and experimental approach, we identified and validated endogenous protein-coding transcripts that regulate PTEN, antagonize PI3K/AKT signaling, and possess growth- and tumor-suppressive properties. Notably, we also show that these genes display concordant expression patterns with PTEN and copy number loss in cancers. Our study presents a road map for the prediction and validation of ceRNA activity and networks and thus imparts a trans-regulatory function to protein-coding mRNAs. Copyright © 2011 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Nat Commun
                Journal ID (iso-abbrev): Nat Commun
                Title: Nature Communications
                Publisher: Nature Publishing Group
                ISSN (Electronic): 2041-1723
                Publication date (Electronic): 15 March 2016
                Publication date Collection: 2016
                Volume: 7
                Electronic Location Identifier: 10982
                Affiliations
                [1 ]Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital , Shanghai 200433, China
                [2 ]Department of Bioinformatics, School of Life Sciences and Technology, Tongji University , Shanghai 200092, China
                [3 ]Department of Medical Oncology, Dana-Farber Cancer Institute , Boston, Massachusetts 02215, USA
                [4 ]Harvard Medical School, Boston , Massachusetts 02215, USA
                [5 ]Department of Pathology, University of Massachusetts Medical School , Worcester, Massachusetts 01655, USA
                [6 ]Department of Molecular and Cellular Biology, Harvard University , Cambridge, Massachusetts 02138, USA
                [7 ]Department of Stem Cell and Regenerative Biology, Harvard University , Cambridge, Massachusetts 02138, USA
                [8 ]Broad Institute of Massachusetts Institute of Technology and Harvard , Cambridge, Massachusetts 02142, USA
                [9 ]Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute , Boston, Massachusetts 02215, USA
                [10 ]Department of Pathology, Beth Israel Deaconess Medical Center , Boston, Massachusetts, USA
                [11 ]Department of Bioinformatics and Computational Biology, Division of Quantitative Sciences, University of Texas MD Anderson Cancer Center , Houston, Texas 77030, USA
                [12 ]Department of Medicine Memorial Sloan Kettering Cancer Center 1275 York Avenue , New York, New York 10065, USA
                [13 ]Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard School of Public Health , Boston, Massachusetts 02215, USA
                Author notes
                [*]

                These authors contributed equally to this work

                Article
                Publisher Item ID: ncomms10982
                DOI: 10.1038/ncomms10982
                PMC ID: 4796315
                PubMed ID: 26975529
                SO-VID: 1da8da58-ab8c-4807-bdb8-466ec0622337
                Copyright © Copyright © 2016, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.
                License:

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                Date received : 13 October 2015
                Date accepted : 09 February 2016
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