Mani RS, Amin MA, Li X, Kalyana-Sundaram S, Veeneman BA, Wang L, Ghosh A, Aslam A, Ramanand SG, Rabquer BJ, Kimura W, Tran M, Cao X, Roychowdhury S, Dhanasekaran SM, Palanisamy N, Sadek HA, Kapur P, Koch AE, and Chinnaiyan AM. Inflammation-induced oxidative stress mediates gene fusion formation in prostate cancer. Cell Rep 2016; 17(10):2620-2631.
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.
Medical Subject Headings
Androgens; Cell Line, Tumor; DNA Breaks; DNA End-Joining Repair; DNA-Binding Proteins; Humans; Inflammation; Male; Oncogene Proteins, Fusion; Oxidative Stress; Prostatic Neoplasms; Serine Endopeptidases; Transcriptional Regulator ERG