Journal
ONCOGENE
Volume 40, Issue 47, Pages 6479-6493Publisher
SPRINGERNATURE
DOI: 10.1038/s41388-021-02026-7
Keywords
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Funding
- National Science Foundation of China [62003094]
- University of Macau [MYRG2018-00033-FHS, MYRG2020-00100-FHS]
- Macau Science and Technology Development Fund [102/2015/A3, 0137/2020/A3, 0011/2019/AKP]
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The study reveals that AR directly regulates a set of signature genes in the ER-to-Golgi transport pathway in PCa, which are essential for cell growth and survival. Inhibiting the ER-to-Golgi transport process enhances the antiandrogen-mediated tumor suppression effect, suggesting a potential therapeutic strategy for advanced PCa.
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.
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