Transcriptional repression activity of androgen receptor targets cell plasticity in prostate cancer: kinetic analysis after DHT treatment

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 dataset 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（Androgen receptor, AR）信号通路仍是激素初治晚期前列腺癌（hormone-naïve advanced prostate cancer, PCa）与去势抵抗性前列腺癌（castration-resistant PCa, CRPC）临床管理的核心治疗靶点。近期研究报道了CRPC的标志性分子特征，包括表达缺乏配体结合域（ligand-binding domain）的组成型激活AR变异体。除在CRPC中发挥作用外，AR变异体还可诱导参与肿瘤进展的基因表达。然而，相较于野生型AR（wild-type AR, AR-WT），学界对AR变异体作用模式的特异性仍知之甚少。本研究在雄激素依赖型PCa细胞系中开展AR转录组分析，并结合公开可用的RNA测序（RNA-seq）数据集进行交叉分析，证实AR-WT所具备的显著转录抑制能力在病理状态下被AR变异体病理性丧失。通过功能富集分析，我们将AR-WT的抑制功能与一组参与细胞黏附及上皮-间质转化（epithelial-to-mesenchymal transition）的基因建立了关联。据此，我们提出假说：前列腺上皮细胞中此前较少被报道的AR-WT正常生理功能，可能是抑制一组与细胞可塑性相关的基因；而在前列腺癌（PCa）中，AR变异体可病理性抵消这一抑制功能。