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

Giuseppina Pisignano, Sara Napoli, Marco Magistri, Sarah N. Mapelli, Chiara Pastori, Stefano Di Marco, Gianluca Civenni, Domenico Albino, Claudia Enriquez, Sara Allegrini, Abhishek Mitra, Gioacchino D’Ambrosio, Maurizia Mello-Grand, Giovanna Chiorino, Ramon Garcia-Escudero, Gabriele Varani, Giuseppina M. Carbone and Carlo V. Catapano ()
Additional contact information
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)
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)
Stefano Di Marco: Tumor Biology and Experimental Therapeutics Program, Institute of Oncology Research (IOR), and Oncology Institute of Southern Switzerland (IOSI)
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)
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)

Nature Communications, 2017, vol. 8, issue 1, 1-16

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms15622

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