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

doi:10.1038/ncomms15622

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

Department of Life Sciences

Research output: Contribution to journal › Article › peer-review

37 Citations (SciVal)

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 language	English
Article number	15622
Journal	Nature Communications
Volume	8
DOIs	https://doi.org/10.1038/ncomms15622
Publication status	Published - 30 May 2017

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Pisignano, G., Napoli, S., Magistri, M., Mapelli, S. N., 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, G. M., & Catapano, C. V. (2017). A promoter-proximal transcript targeted by genetic polymorphism controls E-cadherin silencing in human cancers. Nature Communications, 8, Article 15622. https://doi.org/10.1038/ncomms15622

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

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

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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AU - Pisignano, Giuseppina

AU - Napoli, Sara

AU - Magistri, Marco

AU - Mapelli, Sarah N

AU - Pastori, Chiara

AU - Di Marco, Stefano

AU - Civenni, Gianluca

AU - Albino, Domenico

AU - Enriquez, Claudia

AU - Allegrini, Sara

AU - Mitra, Abhishek

AU - D'Ambrosio, Gioacchino

AU - Mello-Grand, Maurizia

AU - Chiorino, Giovanna

AU - Garcia-Escudero, Ramon

AU - Varani, Gabriele

AU - Carbone, Giuseppina M

AU - Catapano, Carlo V

PY - 2017/5/30

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N2 - 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.

AB - 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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ER -

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

Abstract

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