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

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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

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, [15622]. https://doi.org/10.1038/ncomms15622