Androgen-induced TOP2B-mediated double-strand breaks and prostate cancer gene rearrangements.
Androgen-induced TOP2B-mediated double-strand breaks and prostate cancer gene rearrangements.
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DNA双链断裂（DSB）可导致基因组重排的发展，这是癌症的标志。前列腺癌（PCa）中的TMPRSS 2-ERG基因融合是人类癌症中观察到的最常见的基因组重排之一。我们发现雄激素信号促进雄激素受体（AR）和拓扑异构酶II β（TOP 2B）共同募集到TMPRSS 2-ERG基因组断裂点的位点，触发重组TOP 2B介导的DSB。此外，雄激素刺激导致TMPRSS 2-ERG融合转录物在需要TOP 2B和DSB修复机制组分的过程中从头产生。最后，与正常前列腺上皮不同，前列腺上皮内瘤变（PIN）细胞显示AR和TOP 2B的强共表达。这些发现暗示雄激素诱导的TOP 2B介导的DSB在产生TMPRSS 2-ERG重排中。
DNA double strand breaks (DSB) can lead to development of genomic rearrangements, which are hallmarks of cancer. TMPRSS2-ERG gene fusions in prostate cancer (PCa) are among the most common genomic rearrangements observed in human cancer. We show that androgen signaling promotes co-recruitment of androgen receptor (AR) and topoisomerase II beta (TOP2B) to sites of TMPRSS2-ERG genomic breakpoints, triggering recombinogenic TOP2B-mediated DSB. Furthermore, androgen stimulation resulted in de novo production of TMPRSS2-ERG fusion transcripts in a process requiring TOP2B and components of DSB repair machinery. Finally, unlike normal prostate epithelium, prostatic intraepithelial neoplasia (PIN) cells showed strong co-expression of AR and TOP2B. These findings implicate androgen-induced TOP2B-mediated DSB in generating TMPRSS2-ERG rearrangements.
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