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

Journal article

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.

Authors: Pisignano, G; Napoli, S; Magistri, M; Mapelli, SN; Pastori, C

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Nature Research
• Journal: Nature Communications
• Volume: 8
• Issue: 1
• Pages: 15622-15622
• Publication date: 2017-05-30
• DOI: 10.1038/ncomms15622
• EISSN: 2041-1723
• ISSN: 2041-1723
• Language: English
• Keywords: Dicer; microRNA; Biology; RNA interference; Epigenetics; Argonaute; Gene; Long non-coding RNA; Promoter; Gene silencing; Gene expression; RNA; Genetics; Cancer research