1. A promoter-proximal transcript targeted by genetic polymorphism controls E-cadherin silencing in human cancers.
- Author
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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, and Catapano CV
- Subjects
- Alleles, Antigens, CD, Cell Differentiation, Epigenesis, Genetic, Gene Expression Regulation, Neoplastic, Genes, Tumor Suppressor, Humans, Male, Mutagenesis, Site-Directed, Nucleic Acid Conformation, Polymorphism, Genetic, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Prostatic Neoplasms metabolism, Argonaute Proteins genetics, Cadherins genetics, Eukaryotic Initiation Factors genetics, Gene Silencing, Methyltransferases genetics, Neoplasms genetics, Prostatic Neoplasms genetics, Repressor Proteins genetics
- 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.
- Published
- 2017
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