CNRS UMR 7104, INSERM U1258, IGBMC, University de Strasbourg, Illkirch, France.
University of Freiburg, Freiburg im Breisgau, Germany.
Mol Oncol. 2022 Jul;16(13):2518-2536. doi: 10.1002/1878-0261.13164. Epub 2022 Feb 2.
Androgen receptor (AR) signaling remains the key therapeutic target in the management of hormone-naïve-advanced prostate cancer (PCa) and castration-resistant PCa (CRPC). Recently, landmark molecular features have been reported for CRPC, including the expression of constitutively active AR variants that lack the ligand-binding domain. Besides their role in CRPC, AR variants lead to the expression of genes involved in tumor progression. However, little is known about the specificity of their mode of action compared with that of wild-type AR (AR-WT). We performed AR transcriptome analyses in an androgen-dependent PCa cell line as well as cross-analyses with publicly available RNA-seq datasets and established that transcriptional repression capacity that was marked for AR-WT was pathologically lost by AR variants. Functional enrichment analyses allowed us to associate AR-WT repressive function to a panel of genes involved in cell adhesion and epithelial-to-mesenchymal transition. So, we postulate that a less documented AR-WT normal function in prostate epithelial cells could be the repression of a panel of genes linked to cell plasticity and that this repressive function could be pathologically abrogated by AR variants in PCa.
雄激素受体（AR）信号仍然是激素初治晚期前列腺癌（PCa）和去势抵抗性 PCa（CRPC）治疗的关键靶点。最近，CRPC 的标志性分子特征已经被报道，包括表达缺乏配体结合域的组成型激活 AR 变体。除了在 CRPC 中的作用外，AR 变体还导致参与肿瘤进展的基因的表达。然而，与野生型 AR（AR-WT）相比，它们的作用模式特异性知之甚少。我们在雄激素依赖性 PCa 细胞系中进行了 AR 转录组分析，并与公开可用的 RNA-seq 数据集进行了交叉分析，结果表明，AR 变体标记的 AR-WT 的转录抑制能力病理性丧失。功能富集分析使我们能够将 AR-WT 的抑制功能与一组参与细胞黏附和上皮-间充质转化的基因联系起来。因此，我们假设在前列腺上皮细胞中，AR-WT 的一个较少被记录的正常功能可能是对一组与细胞可塑性相关的基因的抑制，而这种抑制功能可能在 PCa 中被 AR 变体病理性破坏。
