A somatically acquired enhancer of the androgen receptor is a noncoding driver in advanced prostate cancer. A somatically acquired enhancer of the androgen receptor is a noncoding driver in advanced prostate cancer

Increased androgen receptor (AR) activity drives therapeutic resistance in advanced prostate cancer. The most common resistance mechanism is amplification of this locus presumably targeting the AR gene. Here, we identify and characterize a somatically acquired AR enhancer located 650 kilobases centromeric to the AR. Systematic perturbation of this enhancer using genome editing decreased proliferation by suppressing AR levels. Insertion of an additional copy of this region sufficed to increase proliferation under low androgen conditions and to decrease sensitivity to enzalutamide. Epigenetic data generated in localized prostate tumors and benign specimens support the notion that this region is a developmental enhancer. Collectively, these observations underscore the importance of epigenomic profiling in primary specimens and the value of deploying genome editing to functionally characterize noncoding elements. More broadly, this work identifies a therapeutic vulnerability for targeting the AR and emphasizes the importance of regulatory elements as highly recurrent oncogenic drivers. Overall design: Examination of H3K4me2 in 4 patient tumors, H3K27me3 in 4 patient tumors, H3K27Ac in 11 patient tumors, HOXB13 in 4 patient tumors, FOXA1 in 4 patient tumors

雄激素受体（androgen receptor, AR）活性增强可驱动晚期前列腺癌产生治疗抵抗。最为常见的耐药机制为该基因座的扩增，推测其靶向AR基因。本研究鉴定并表征了一个定位于AR基因着丝粒侧650千碱基对（kilobases）的体细胞获得性AR增强子。通过基因组编辑对该增强子开展系统性扰动，可通过抑制AR表达水平降低细胞增殖能力。插入该区域的额外拷贝足以在低雄激素条件下促进细胞增殖，并降低对恩扎卢胺（enzalutamide）的敏感性。在局限性前列腺肿瘤与良性标本中获取的表观基因组数据，支持该区域属于发育增强子的观点。综上，这些研究结果突显了对原发标本进行表观基因组谱分析的重要性，以及利用基因组编辑实现非编码元件功能表征的价值。从更广泛的视角来看，本研究鉴定出了靶向AR的治疗易感位点，并强调了调控元件作为高频致癌驱动因子的关键作用。

总体实验设计：对4例患者肿瘤的组蛋白H3赖氨酸4二甲基化（H3K4me2）、4例患者肿瘤的组蛋白H3赖氨酸27三甲基化（H3K27me3）、11例患者肿瘤的组蛋白H3赖氨酸27乙酰化（H3K27Ac）、4例患者肿瘤的HOXB13以及4例患者肿瘤的FOXA1进行检测。