Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; The Eli and Edythe L. Broad Institute, Cambridge, MA 02142, USA.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Cell. 2018 Jul 12;174(2):422-432.e13. doi: 10.1016/j.cell.2018.05.037. Epub 2018 Jun 14.
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 kb 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.
雄激素受体 (AR) 活性增加会导致晚期前列腺癌的治疗耐药。最常见的耐药机制是该基因座的扩增，可能针对 AR 基因。在这里，我们鉴定并表征了一个位于 AR 着丝粒 650kb 内的体细胞获得的 AR 增强子。使用基因组编辑系统地扰动该增强子会通过抑制 AR 水平来抑制增殖。插入该区域的额外拷贝足以在低雄激素条件下增加增殖，并降低对恩扎卢胺的敏感性。在局部前列腺肿瘤和良性标本中生成的表观遗传数据支持该区域是发育增强子的观点。总的来说，这些观察结果强调了在原发性标本中进行表观基因组分析的重要性，以及利用基因组编辑来对非编码元件进行功能表征的价值。更广泛地说，这项工作确定了针对 AR 的治疗弱点，并强调了调控元件作为高度复发致癌驱动因素的重要性。
