Single-cell analysis reveals androgen receptor regulates the ER-to-Golgi trafficking pathway with CREB3L2 to drive prostate cancer progression

• Published in: Oncogene 2021-11, Vol.40 (47), p.6479-6493
• Main Authors: Hu, Lingling, Chen, Xin, Narwade, Nitin, Lim, Michelle Gek Liang, Chen, Zikai, Tennakoon, Chandana, Guan, Peiyong, Chan, Un In, Zhao, Zuxianglan, Deng, Mokan, Xu, Xiaoling, Sung, Wing-Kin, Cheung, Edwin
• Format: Article
• Language: English
• Subjects: 13; 14; 38; 45; 631/337/572; 631/67/589/466; 82; 96; Androgen receptors; Androgens; Androgens - pharmacology; Animals; Apoptosis; Basic-Leucine Zipper Transcription Factors - genetics; Basic-Leucine Zipper Transcription Factors - metabolism; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Cell Biology; Cell Proliferation; Cell survival; Cellular signal transduction; Development and progression; Endoplasmic reticulum; Endoplasmic Reticulum - drug effects; Endoplasmic Reticulum - metabolism; Endoplasmic Reticulum - pathology; Gene Expression Regulation, Neoplastic - drug effects; Gene Regulatory Networks; Genetic aspects; Golgi apparatus; Golgi Apparatus - drug effects; Golgi Apparatus - metabolism; Golgi Apparatus - pathology; Health aspects; Human Genetics; Humans; Internal Medicine; Male; Medical prognosis; Medicine; Medicine & Public Health; Mice; Oncology; Prognosis; Prostate cancer; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Protein transport; Receptors, Androgen - genetics; Receptors, Androgen - metabolism; Single-Cell Analysis - methods; Survival Rate; Transcription; Transcriptome; Transcriptomes; Tumor Cells, Cultured; Tumor suppression; Tumors; Xenograft Model Antitumor Assays
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-021-02026-7

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.