PIWI-interacting RNA 021285 is involved in breast tumorigenesis possibly by remodeling the cancer epigenome

Carcinogenesis. 2015 Oct;36(10):1094-102. doi: 10.1093/carcin/bgv105. Epub 2015 Jul 25.

Abstract

Although PIWI-interacting RNAs (piRNAs) account for the largest class of the small non-coding RNA superfamily, virtually nothing is known of their function in human carcinogenesis. Once thought to be expressed solely in the germ line where they safeguard the genome against transposon-induced insertional mutations, piRNAs are now believed to play an active role in somatic gene regulation through sequence-specific histone modification and DNA methylation. In the current study, we investigate the role of piRNA-021285 (piR-021285) in the regulation of the breast cancer methylome. Genotypic screening of a panel of single-nucleotide polymorphism (SNP)-containing piRNAs revealed a significant association between SNP rs1326306 G>T in piR-021285 and increased likelihood for breast cancer in a Connecticut-based population (441 cases and 479 controls). Given nascent but compelling evidence of piRNA-mediated gene-specific methylation in the soma, a genome-wide methylation screen was then carried out using wild type (WT) and variant piR-021285 mimic-transfected MCF7 cells to explore whether the observed association could be attributed in part to piR-021285-induced methylation at cancer-relevant genes. We found significant methylation differences at a number of experimentally implicated breast cancer-related genes, including attenuated 5' untranslated region (UTR)/first exon methylation at the proinvasive ARHGAP11A gene in variant mimic-transfected cells. Follow-up functional analyses revealed both concurrent increased ARHGAP11A mRNA expression and enhanced invasiveness in variant versus WT piR-021285 mimic-transfected breast cancer cell lines. Taken together, our findings demonstrate the first evidence supporting a role of piRNAs, a novel group of non-coding RNA, in human tumorigenesis via a piRNA-mediated epigenetic mechanism, which warrants further confirmation and investigation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology
  • Carcinogenesis*
  • DNA Methylation / genetics*
  • Epigenesis, Genetic / genetics
  • Female
  • GTPase-Activating Proteins / genetics
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Neoplasm Invasiveness / genetics
  • Polymorphism, Single Nucleotide
  • RNA, Small Interfering / genetics*
  • RNA, Small Untranslated / genetics*

Substances

  • ARHGAP11A protein, human
  • GTPase-Activating Proteins
  • RNA, Small Interfering
  • RNA, Small Untranslated