A non-coding RNA network influenced by genetic polymorphism controls E-cadherin expression in human cancers

Abstract

Reduced expression of E-cadherin, encoded by the CDH1 gene, is frequent in epithelial tumours and is associated with the acquisition of invasive, stem cell-like and metastatic properties. However, the molecular mechanisms underlying the loss of E-cadherin expression are not fully understood. In this project, we uncover a complex network comprising a promoter- associated noncoding RNA (paRNA), microRNA and epigenetic regulators that controls transcription of 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. Notably, we found that 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.