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A promoter-proximal transcript targeted by genetic polymorphism controls E-cadherin silencing in human cancers

Author

Listed:
  • Giuseppina Pisignano

    (Tumor Biology and Experimental Therapeutics Program, Institute of Oncology Research (IOR), and Oncology Institute of Southern Switzerland (IOSI))

  • Sara Napoli

    (Tumor Biology and Experimental Therapeutics Program, Institute of Oncology Research (IOR), and Oncology Institute of Southern Switzerland (IOSI))

  • Marco Magistri

    (Tumor Biology and Experimental Therapeutics Program, Institute of Oncology Research (IOR), and Oncology Institute of Southern Switzerland (IOSI)
    Present address: Department of Psychiatry and Behavioral Sciences, Center for Therapeutic Innovation, University of Miami Miller School of Medicine, Miami, Florida 33136, USA)

  • Sarah N. Mapelli

    (Tumor Biology and Experimental Therapeutics Program, Institute of Oncology Research (IOR), and Oncology Institute of Southern Switzerland (IOSI))

  • Chiara Pastori

    (Tumor Biology and Experimental Therapeutics Program, Institute of Oncology Research (IOR), and Oncology Institute of Southern Switzerland (IOSI)
    Present address: Department of Psychiatry and Behavioral Sciences, Center for Therapeutic Innovation, University of Miami Miller School of Medicine, Miami, Florida 33136, USA)

  • Stefano Di Marco

    (Tumor Biology and Experimental Therapeutics Program, Institute of Oncology Research (IOR), and Oncology Institute of Southern Switzerland (IOSI)
    Present address: IMCR, University of Zurich, 8057 Zurich, Switzerland)

  • Gianluca Civenni

    (Tumor Biology and Experimental Therapeutics Program, Institute of Oncology Research (IOR), and Oncology Institute of Southern Switzerland (IOSI))

  • Domenico Albino

    (Tumor Biology and Experimental Therapeutics Program, Institute of Oncology Research (IOR), and Oncology Institute of Southern Switzerland (IOSI))

  • Claudia Enriquez

    (Tumor Biology and Experimental Therapeutics Program, Institute of Oncology Research (IOR), and Oncology Institute of Southern Switzerland (IOSI))

  • Sara Allegrini

    (Tumor Biology and Experimental Therapeutics Program, Institute of Oncology Research (IOR), and Oncology Institute of Southern Switzerland (IOSI))

  • Abhishek Mitra

    (Tumor Biology and Experimental Therapeutics Program, Institute of Oncology Research (IOR), and Oncology Institute of Southern Switzerland (IOSI))

  • Gioacchino D’Ambrosio

    (IRCCS Multimedica)

  • Maurizia Mello-Grand

    (Laboratory of Cancer Genomics, Fondo Edo Tempia)

  • Giovanna Chiorino

    (Laboratory of Cancer Genomics, Fondo Edo Tempia)

  • Ramon Garcia-Escudero

    (Tumor Biology and Experimental Therapeutics Program, Institute of Oncology Research (IOR), and Oncology Institute of Southern Switzerland (IOSI)
    Molecular Oncology Unit, CIEMAT and Centro de Investigación Biomédica en Red de Cáncer (CIBERONC))

  • Gabriele Varani

    (University of Washington)

  • Giuseppina M. Carbone

    (Tumor Biology and Experimental Therapeutics Program, Institute of Oncology Research (IOR), and Oncology Institute of Southern Switzerland (IOSI))

  • Carlo V. Catapano

    (Tumor Biology and Experimental Therapeutics Program, Institute of Oncology Research (IOR), and Oncology Institute of Southern Switzerland (IOSI)
    Faculty of Biology and Medicine, University of Lausanne)

Abstract

Long noncoding RNAs are emerging players in the epigenetic machinery with key roles in development and diseases. Here we uncover a complex network comprising a promoter-associated noncoding RNA (paRNA), microRNA and epigenetic regulators that controls transcription of the tumour suppressor E-cadherin in epithelial cancers. E-cadherin silencing relies on the formation of a complex between the paRNA and microRNA-guided Argonaute 1 that, together, recruit SUV39H1 and induce repressive chromatin modifications in the gene promoter. A single nucleotide polymorphism (rs16260) linked to increased cancer risk alters the secondary structure of the paRNA, with the risk allele facilitating the assembly of the microRNA-guided Argonaute 1 complex and gene silencing. Collectively, these data demonstrate the role of a paRNA in E-cadherin regulation and the impact of a noncoding genetic variant on its function. Deregulation of paRNA-based epigenetic networks may contribute to cancer and other diseases making them promising targets for drug discovery.

Suggested Citation

  • Giuseppina Pisignano & Sara Napoli & Marco Magistri & Sarah N. Mapelli & Chiara Pastori & Stefano Di Marco & Gianluca Civenni & Domenico Albino & Claudia Enriquez & Sara Allegrini & Abhishek Mitra & G, 2017. "A promoter-proximal transcript targeted by genetic polymorphism controls E-cadherin silencing in human cancers," Nature Communications, Nature, vol. 8(1), pages 1-16, August.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms15622
    DOI: 10.1038/ncomms15622
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