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

Nat Commun. 2017 May 30:8:15622. doi: 10.1038/ncomms15622.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Antigens, CD
  • Argonaute Proteins / genetics*
  • Cadherins / genetics*
  • Cell Differentiation
  • Epigenesis, Genetic
  • Eukaryotic Initiation Factors / genetics*
  • Gene Expression Regulation, Neoplastic
  • Gene Silencing*
  • Genes, Tumor Suppressor
  • Humans
  • Male
  • Methyltransferases / genetics*
  • Mutagenesis, Site-Directed
  • Neoplasms / genetics*
  • Nucleic Acid Conformation
  • Polymorphism, Genetic
  • Polymorphism, Single Nucleotide
  • Promoter Regions, Genetic
  • Prostatic Neoplasms / genetics*
  • Prostatic Neoplasms / metabolism
  • Repressor Proteins / genetics*

Substances

  • AGO1 protein, human
  • Antigens, CD
  • Argonaute Proteins
  • CDH1 protein, human
  • Cadherins
  • Eukaryotic Initiation Factors
  • Repressor Proteins
  • SUV39H1 protein, human
  • Methyltransferases