Epigenetic processes govern prostate cancer (PCa) biology, as evidenced by the dependency of PCa cells on the androgen receptor (AR), a prostate master transcription factor. We generated 268 epigenomic datasets spanning two state transitions—from normal prostate epithelium to localized PCa to metastases—in specimens derived from human tissue. We discovered that reprogrammed AR sites in metastatic PCa are not created de novo; rather, they are prepopulated by the transcription factors FOXA1 and HOXB13 in normal prostate epithelium. Reprogrammed regulatory elements commissioned in metastatic disease hijack latent developmental programs, accessing sites that are implicated in prostate organogenesis. Analysis of reactivated regulatory elements enabled the identification and functional validation of previously unknown metastasis-specific enhancers at HOXB13, FOXA1 and NKX3-1. Finally, we observed that prostate lineage-specific regulatory elements were strongly associated with PCa risk heritability and somatic mutation density. Examining prostate biology through an epigenomic lens is fundamental for understanding the mechanisms underlying tumor progression.

表观遗传过程控制前列腺癌 (PCa) 生物学，PCa 细胞对雄激素受体 (AR)（一种前列腺主转录因子）的依赖性证明了这一点。我们在源自人体组织的标本中生成了 268 个表观基因组数据集，跨越两个状态转变——从正常前列腺上皮细胞到局部前列腺癌再到转移瘤。我们发现转移性 PCa 中重新编程的 AR 位点不是从头创建的；相反，它们是由正常前列腺上皮细胞中的转录因子 FOXA1 和 HOXB13 预先填充的。转移性疾病中委托的重新编程的调控元件劫持了潜在的发育程序，访问了与前列腺器官发生有关的位点。对重新激活的调节元件的分析能够识别和验证以前未知的转移特异性增强子HOXB13、FOXA1和NKX3-1。最后，我们观察到前列腺谱系特异性调节元件与 PCa 风险遗传性和体细胞突变密度密切相关。通过表观基因组镜头检查前列腺生物学对于理解肿瘤进展的潜在机制至关重要。