Chen Xuanrong, Augello Michael A, Liu Deli, Lin Kevin, Hakansson Alex, Sjöström Martin, Khani Francesca, Deonarine Lesa D, Liu Yang, Travascio-Green Jaida, Wu Jiansheng, Chan Un In, Owiredu Jude, Loda Massimo, Feng Felix Y, Robinson Brian D, Davicioni Elai, Sboner Andrea, Barbieri Christopher E
Department of Urology, Weill Cornell Medicine, New York, NY, USA.
Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.
Nat Commun. 2024 Dec 13;15(1):10675. doi: 10.1038/s41467-024-53734-z.
The androgen receptor (AR) is central in prostate tissue identity and differentiation, and controls normal growth-suppressive, prostate-specific gene expression. It also drives prostate tumorigenesis when hijacked for oncogenic transcription. The execution of growth-suppressive AR transcriptional programs in prostate cancer (PCa) and the potential for reactivation remain unclear. Here, we use a genome-wide approach to modulate canonical androgen response element (ARE) motifs-the classic DNA binding elements for AR-to delineate distinct AR transcriptional programs. We find that activating these AREs promotes differentiation and growth-suppressive transcription, potentially leading to AR PCa cell death, while ARE repression is tolerated by PCa cells but deleterious to normal prostate cells. Gene signatures driven by ARE activity correlate with improved prognosis and luminal phenotypes in PCa patients. Canonical AREs maintain a normal, lineage-specific transcriptional program that can be reengaged in PCa cells, offering therapeutic potential and clinical relevance.
雄激素受体（AR）在前列腺组织特性和分化中起核心作用，并控制正常的生长抑制性前列腺特异性基因表达。当被用于致癌转录时，它还会驱动前列腺肿瘤发生。前列腺癌（PCa）中生长抑制性AR转录程序的执行情况以及重新激活的可能性仍不清楚。在这里，我们使用全基因组方法来调节典型雄激素反应元件（ARE）基序——AR的经典DNA结合元件——以描绘不同的AR转录程序。我们发现激活这些ARE会促进分化和生长抑制性转录，可能导致AR PCa细胞死亡，而ARE抑制则为PCa细胞所耐受，但对正常前列腺细胞有害。由ARE活性驱动的基因特征与PCa患者预后改善和管腔表型相关。典型ARE维持着一种正常的、谱系特异性转录程序，该程序可在PCa细胞中重新启动，具有治疗潜力和临床相关性。
