| Literature DB >> 27926866 |
Ram S Mani1, Mohammad A Amin2, Xiangyi Li3, Shanker Kalyana-Sundaram4, Brendan A Veeneman5, Lei Wang4, Aparna Ghosh4, Adam Aslam3, Susmita G Ramanand3, Bradley J Rabquer2, Wataru Kimura6, Maxwell Tran4, Xuhong Cao7, Sameek Roychowdhury8, Saravana M Dhanasekaran4, Nallasivam Palanisamy9, Hesham A Sadek10, Payal Kapur11, Alisa E Koch12, Arul M Chinnaiyan13.
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.Entities:
Keywords: DNA breaks; NHEJ; ROS; TMPRSS2-ERG; TNF; gene fusion; inflammation; microhomology; oxidative stress; prostate cancer
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Year: 2016 PMID： 27926866 PMCID： PMC5147555 DOI： 10.1016/j.celrep.2016.11.019
Source DB: PubMed Journal: Cell Rep Impact factor: 9.423