TY - JOUR
T1 - A promoter-proximal transcript targeted by genetic polymorphism controls E-cadherin silencing in human cancers
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
Y1 - 2017/5/30
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.
U2 - 10.1038/ncomms15622
DO - 10.1038/ncomms15622
M3 - Article
C2 - 28555645
SN - 2041-1723
VL - 8
JO - Nature Communications
JF - Nature Communications
M1 - 15622
ER -
