Inflammation-Induced Oxidative Stress Mediates Gene Fusion Formation in Prostate Cancer.
Abstact
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.
Authors
- Amin MA
- Aslam A
- Cao X
- Chinnaiyan AM
- Dhanasekaran SM
- Ghosh A
- Kalyana-Sundaram S
- Kapur P
- Kimura W
- Koch AE
- Li X
- Mani RS
- Palanisamy N
- Rabquer BJ
- Ramanand SG
- Roychowdhury S
- Sadek HA
- Tran M
- Veeneman BA
- Wang L