Inflammation-Induced Oxidative Stress Mediates Gene Fusion Formation in Prostate Cancer.
Inflammation-Induced Oxidative Stress Mediates Gene Fusion Formation in Prostate Cancer.
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DOI：
10.1016/j.celrep.2016.11.019
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发表时间：
2016-12-06
期刊：
影响因子：
8.8
通讯作者：
Chinnaiyan AM
中科院分区：
文献类型：
--
作者：
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;Chinnaiyan AM
大约50%的前列腺癌与雄激素调节基因TMPRSS 2与致癌ETS转录因子ERG的基因融合有关。TMPRSS 2和ERG基因的三维接近性与DNA断裂组合促进TMPRSS 2-ERG基因融合体的形成。然而，前列腺癌中基因融合形成的基础DNA断裂的起源还远不清楚。我们证明了炎症诱导的氧化应激在导致TMPRSS 2-ERG基因融合复发的DNA断裂形成中的作用。靶基因的转录状态和表观遗传特征影响这种效应。重要的是，炎症诱导的从头基因组重排被同源重组（HR）阻断，并被非同源末端连接（NHEJ）途径促进。结合增生性炎性萎缩（PIA）与人前列腺癌的相关性，我们的研究结果支持了一个工作模型，其中炎症刺激诱导的复发性基因组重排导致前列腺癌的发展。虽然在文献中有相当多的证据将炎症与前列腺癌的发展联系起来，但很少有与复发性驱动基因突变的直接联系。Mani等人发现炎症诱导的氧化应激在导致复发性TMPRSS 2-ERG基因融合的DNA断裂形成中的作用。
Approximately 50% of prostate cancers are associated with gene fusions of the androgen-regulated gene, TMPRSS2, to the oncogenic ETS transcription factor, ERG. The three-dimensional proximity of TMPRSS2 and ERG genes, in combination with DNA breaks facilitate 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 leads to the development of prostate cancer. While there is considerable evidence in the literature linking inflammation to the development of prostate cancer, there are few direct links to recurrent driver gene mutations. Mani et al. find a role for inflammation-induced oxidative stress in the formation of DNA breaks leading to recurrent TMPRSS2-ERG gene fusions.
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