Cancer Centre, University of Macau, Taipa, Macau SAR.
Centre for Precision Medicine Research and Training, University of Macau, Taipa, Macau SAR.
Oncogene. 2021 Nov;40(47):6479-6493. doi: 10.1038/s41388-021-02026-7. Epub 2021 Oct 5.
Androgen receptor (AR) plays a central role in driving prostate cancer (PCa) progression. How AR promotes this process is still not completely clear. Herein, we used single-cell transcriptome analysis to reconstruct the transcriptional network of AR in PCa. Our work shows AR directly regulates a set of signature genes in the ER-to-Golgi protein vesicle-mediated transport pathway. The expression of these genes is required for maximum androgen-dependent ER-to-Golgi trafficking, cell growth, and survival. Our analyses also reveal the signature genes are associated with PCa progression and prognosis. Moreover, we find inhibition of the ER-to-Golgi transport process with a small molecule enhanced antiandrogen-mediated tumor suppression of hormone-sensitive and insensitive PCa. Finally, we demonstrate AR collaborates with CREB3L2 in mediating ER-to-Golgi trafficking in PCa. In summary, our findings uncover a critical role for dysregulation of ER-to-Golgi trafficking expression and function in PCa progression, provide detailed mechanistic insights for how AR tightly controls this process, and highlight the prospect of targeting the ER-to-Golgi pathway as a therapeutic strategy for advanced PCa.
雄激素受体（AR）在推动前列腺癌（PCa）进展中起着核心作用。AR 如何促进这一过程尚不完全清楚。在此，我们使用单细胞转录组分析重建了 PCa 中 AR 的转录网络。我们的工作表明，AR 直接调控内质网到高尔基体蛋白囊泡介导的运输途径中一组特征基因。这些基因的表达对于最大程度的雄激素依赖性内质网到高尔基体运输、细胞生长和存活是必需的。我们的分析还揭示了这些特征基因与 PCa 的进展和预后相关。此外，我们发现用小分子抑制内质网到高尔基体的运输过程，增强了抗雄激素对激素敏感和不敏感 PCa 的肿瘤抑制作用。最后，我们证明 AR 与 CREB3L2 合作在介导 PCa 中的内质网到高尔基体运输中起作用。总之，我们的发现揭示了内质网到高尔基体运输表达和功能失调在 PCa 进展中的关键作用，为 AR 如何严格控制这一过程提供了详细的机制见解，并强调了靶向内质网到高尔基体途径作为晚期 PCa 治疗策略的前景。
