Single-Cell Analysis Reveals Androgen Receptor Regulates ER-to-Golgi Trafficking with CREB3L2 To Drive Prostate Cancer Progression

Androgen receptor (AR) plays an essential role in normal prostate development and prostate cancer (PCa) progression. To understand the role of AR at the single-cell level, we performed single-cell transcriptome analysis on PCa cells stimulated with androgen and antiandrogen to reconstruct the dynamic and direct AR transcriptional network. Our work reveals that androgen stimulates the ER and Golgi stress response , promoting secreting protein trafficking, and inhibiting cell apoptosis. Moreover, we identify an ER-to-Golgi protein vesicle-mediated transport gene signature essential for maximal androgen-mediated ER-Golgi trafficking, cell proliferation, and association with PCa prognosis and progression. Notably, we show that AR collaborates with CREB3L2, XXX, to coordinately promote ER-Golgi trafficking of Golgi enzyme Mannosidase II and PCa cell survival. Finally, we show the inhibition of the ER-Golgi transport process with Brefeldin A leads to tumor regression. Our study collectively reveals the heterogeneity of PCa cell transcriptional response to androgen stimulation, demonstrates a functional role for increased ER-Golgi trafficking process, and provides a mechanism for how the process is augmented in PCa as well as the potential of targeting may provide novel treatment strategies. Overall design: VCaP cells were treated with either ethanol (vehicle) or 100nM DHT for 2h, before being harvested for ChIP assay.