Inflammation-Induced Oxidative Stress Mediates Gene Fusion Formation in Prostate Cancer

Cell Rep. 2016 Dec 6;17(10):2620-2631. doi: 10.1016/j.celrep.2016.11.019.

Abstract

Approximately 50% of prostate cancers are associated with gene fusions of the androgen-regulated gene TMPRSS2 to the oncogenic erythroblast transformation-specific (ETS) transcription factor ERG. The three-dimensional proximity of TMPRSS2 and ERG genes, in combination with DNA breaks, facilitates the formation of TMPRSS2-ERG gene fusions. However, the origins of DNA breaks that underlie gene fusion formation in prostate cancers are far from clear. We demonstrate a role for inflammation-induced oxidative stress in the formation of DNA breaks leading to recurrent TMPRSS2-ERG gene fusions. The transcriptional status and epigenetic features of the target genes influence this effect. Importantly, inflammation-induced de novo genomic rearrangements are blocked by homologous recombination (HR) and promoted by non-homologous end-joining (NHEJ) pathways. In conjunction with the association of proliferative inflammatory atrophy (PIA) with human prostate cancer, our results support a working model in which recurrent genomic rearrangements induced by inflammatory stimuli lead to the development of prostate cancer.

Keywords: DNA breaks; NHEJ; ROS; TMPRSS2-ERG; TNF; gene fusion; inflammation; microhomology; oxidative stress; prostate cancer.

Publication types

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

MeSH terms

  • Androgens / genetics
  • Cell Line, Tumor
  • DNA Breaks
  • DNA End-Joining Repair / genetics
  • DNA-Binding Proteins / genetics
  • Humans
  • Inflammation / complications
  • Inflammation / genetics*
  • Inflammation / pathology
  • Male
  • Oncogene Proteins, Fusion / genetics*
  • Oxidative Stress / genetics
  • Prostatic Neoplasms / complications
  • Prostatic Neoplasms / genetics*
  • Prostatic Neoplasms / pathology
  • Serine Endopeptidases / genetics*
  • Transcriptional Regulator ERG / genetics

Substances

  • Androgens
  • DNA-Binding Proteins
  • ERG protein, human
  • Oncogene Proteins, Fusion
  • Transcriptional Regulator ERG
  • Serine Endopeptidases
  • TMPRSS2 protein, human