Department of Medicine, Center for Pharmacogenomics, Washington University School of Medicine, St. Louis, MO 63110, USA.
Nucleic Acids Res. 2012 Nov;40(21):10765-79. doi: 10.1093/nar/gks888. Epub 2012 Sep 27.
The androgen receptor (AR) is a ligand-inducible transcription factor that mediates androgen action in target tissues. Upon ligand binding, the AR binds to thousands of genomic loci and activates a cell-type specific gene program. Prostate cancer growth and progression depend on androgen-induced AR signaling. Treatment of advanced prostate cancer through medical or surgical castration leads to initial response and durable remission, but resistance inevitably develops. In castration-resistant prostate cancer (CRPC), AR activity remains critical for tumor growth despite androgen deprivation. Although previous studies have focused on ligand-dependent AR signaling, in this study we explore AR function under the androgen-deprived conditions characteristic of CRPC. Our data demonstrate that AR persistently occupies a distinct set of genomic loci after androgen deprivation in CRPC. These androgen-independent AR occupied regions have constitutively open chromatin structures that lack the canonical androgen response element and are independent of FoxA1, a transcription factor involved in ligand-dependent AR targeting. Many AR binding events occur at proximal promoters, which can act as enhancers to augment transcriptional activities of other promoters through DNA looping. We further show that androgen-independent AR binding directs a gene expression program in CRPC, which is necessary for the growth of CRPC after androgen withdrawal.
雄激素受体 (AR) 是一种配体诱导的转录因子，可介导雄激素在靶组织中的作用。配体结合后，AR 结合到数千个基因组位置并激活细胞类型特异性基因程序。前列腺癌的生长和进展依赖于雄激素诱导的 AR 信号。通过医学或手术去势治疗晚期前列腺癌可导致初始反应和持久缓解，但不可避免地会产生耐药性。在去势抵抗性前列腺癌 (CRPC) 中，尽管雄激素剥夺，AR 活性仍然对肿瘤生长至关重要。尽管先前的研究集中在配体依赖性 AR 信号上，但在这项研究中，我们探讨了 CRPC 中雄激素剥夺条件下 AR 的功能。我们的数据表明，在 CRPC 中雄激素剥夺后，AR 持续占据一组独特的基因组位置。这些雄激素非依赖性 AR 占据的区域具有组成型开放的染色质结构，缺乏经典的雄激素反应元件，并且不依赖于 FoxA1，FoxA1 是一种参与配体依赖性 AR 靶向的转录因子。许多 AR 结合事件发生在近端启动子，这些启动子可以作为增强子，通过 DNA 环化增强其他启动子的转录活性。我们进一步表明，雄激素非依赖性 AR 结合指导 CRPC 中的基因表达程序，这是雄激素撤退后 CRPC 生长所必需的。
