RNA-seq in LNCaP with inducible expression of MACC constructs.

The androgen receptor (AR) is the central determinant of prostate tissue identity and differentiation, controlling normal, growth-suppressive prostate-specific gene expression. It is also a key driver of prostate tumorigenesis, becoming “hijacked” to drive oncogenic transcription. However, the regulatory elements determining the execution of the growth suppressive AR transcriptional program, and whether this can be reactivated in prostate cancer (PCa) cells remains unclear. Canonical androgen response element (ARE) motifs are the classic DNA binding element for AR. Here, we used a genome-wide strategy to modulate regulatory elements containing AREs to define distinct AR transcriptional programs. We find that activation of these AREs is specifically associated with differentiation and growth suppressive transcription, and this can be reactivated to cause death in AR+ PCa cells. In contrast, repression of AREs is well tolerated by PCa cells, but deleterious to normal prostate cells. Finally, gene expression signatures driven by ARE activity are associated with improved prognosis and luminal phenotypes in human PCa patients. This study demonstrates that canonical AREs are responsible for a normal, growth-suppressive, lineage-specific transcriptional program, that this can be reengaged in PCa cells for potential therapeutic benefit, and genes controlled by this mechanism are clinically relevant in human PCa patients. Gene expression profiling with RNA-seq in LNCaP with inducible expression of MACC constructs.

雄激素受体（androgen receptor, AR）是决定前列腺组织身份与分化的核心因子，可调控正常的、具有生长抑制作用的前列腺特异性基因表达。其同时也是前列腺肿瘤发生的关键驱动因子，会被“劫持”以介导致癌转录。然而，调控生长抑制性AR转录程序执行的调控元件，以及该程序是否可在前列腺癌（prostate cancer, PCa）细胞中被重新激活，目前仍不明确。经典雄激素反应元件（androgen response element, ARE）基序是AR的经典DNA结合元件。本研究采用全基因组策略对携带ARE的调控元件进行靶向调控，以明确不同的AR转录程序。我们发现，此类ARE的激活与细胞分化及生长抑制性转录特异性相关，且该激活过程可被重新诱导，进而导致AR+ PCa细胞死亡。与之相反，PCa细胞对ARE的抑制具有较好耐受性，但该抑制过程会对正常前列腺细胞造成损害。最后，由ARE活性驱动的基因表达特征与前列腺癌患者的良好预后及管腔表型（luminal phenotypes）显著相关。本研究证实，经典ARE介导了正常的、具有生长抑制作用的谱系特异性转录程序，且该程序可在PCa细胞中被重新激活以带来潜在治疗获益，同时受该机制调控的基因在前列腺癌患者中具有临床相关性。本研究采用RNA测序（RNA-seq）技术，对诱导表达MACC构建体的LNCaP细胞开展了基因表达谱分析。