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

Ram S. Mani, Mohammad A. Amin, Xiangyi Li, Shanker Kalyana-Sundaram, Brendan A. Veeneman, Lei Wang, Aparna Ghosh, Adam Aslam, Susmita G. Ramanand, Bradley J. Rabquer, Wataru Kimura, Maxwell Tran, Xuhong Cao, Sameek Roychowdhury, Saravana M. Dhanasekaran, Nallasivam Palanisamy, Hesham A. Sadek, Payal Kapur, Alisa E. Koch, Arul M. Chinnaiyan

Research output: Contribution to journalArticle

30 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2620-2631
Number of pages12
JournalCell Reports
Volume17
Issue number10
DOIs
StatePublished - Dec 6 2016

    Fingerprint

Keywords

  • DNA breaks
  • NHEJ
  • ROS
  • TMPRSS2-ERG
  • TNF
  • gene fusion
  • inflammation
  • microhomology
  • oxidative stress
  • prostate cancer

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Mani, R. S., Amin, M. A., Li, X., Kalyana-Sundaram, S., Veeneman, B. A., Wang, L., Ghosh, A., Aslam, A., Ramanand, S. G., Rabquer, B. J., Kimura, W., Tran, M., Cao, X., Roychowdhury, S., Dhanasekaran, S. M., Palanisamy, N., Sadek, H. A., Kapur, P., Koch, A. E., & Chinnaiyan, A. M. (2016). Inflammation-Induced Oxidative Stress Mediates Gene Fusion Formation in Prostate Cancer. Cell Reports, 17(10), 2620-2631. https://doi.org/10.1016/j.celrep.2016.11.019