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, Carlo V Catapano

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Article number15622
JournalNature Communications
Volume8
DOIs
Publication statusPublished - 30 May 2017

Cite this

A promoter-proximal transcript targeted by genetic polymorphism controls E-cadherin silencing in human cancers. / Pisignano, Giuseppina; Napoli, Sara; Magistri, Marco; Mapelli, Sarah N; Pastori, Chiara; Di Marco, Stefano; Civenni, Gianluca; Albino, Domenico; Enriquez, Claudia; Allegrini, Sara; Mitra, Abhishek; D'Ambrosio, Gioacchino; Mello-Grand, Maurizia; Chiorino, Giovanna; Garcia-Escudero, Ramon; Varani, Gabriele; Carbone, Giuseppina M; Catapano, Carlo V.

In: Nature Communications, Vol. 8, 15622, 30.05.2017.

Research output: Contribution to journalArticle

Pisignano, G, Napoli, S, Magistri, M, Mapelli, SN, Pastori, C, Di Marco, S, Civenni, G, Albino, D, Enriquez, C, Allegrini, S, Mitra, A, D'Ambrosio, G, Mello-Grand, M, Chiorino, G, Garcia-Escudero, R, Varani, G, Carbone, GM & Catapano, CV 2017, 'A promoter-proximal transcript targeted by genetic polymorphism controls E-cadherin silencing in human cancers', Nature Communications, vol. 8, 15622. https://doi.org/10.1038/ncomms15622
Pisignano, Giuseppina ; Napoli, Sara ; Magistri, Marco ; Mapelli, Sarah N ; Pastori, Chiara ; Di Marco, Stefano ; Civenni, Gianluca ; Albino, Domenico ; Enriquez, Claudia ; Allegrini, Sara ; Mitra, Abhishek ; D'Ambrosio, Gioacchino ; Mello-Grand, Maurizia ; Chiorino, Giovanna ; Garcia-Escudero, Ramon ; Varani, Gabriele ; Carbone, Giuseppina M ; Catapano, Carlo V. / A promoter-proximal transcript targeted by genetic polymorphism controls E-cadherin silencing in human cancers. In: Nature Communications. 2017 ; Vol. 8.
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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.",
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