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

Abstract

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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Fig. 1: Single-cell RNA-seq analysis of hormone-stimulated PCa cells.
Fig. 2: Androgen stimulates the reprogramming of protein processing and transport in PCa cells.
Fig. 3: Androgen induction of an ER-to-Golgi vesicle-mediated transport gene signature correlates with AR activity, progression, and recurrence-free survival in PCa patients.
Fig. 4: AR directly up-regulates the transcription of the ER-to-Golgi vesicle-mediated transport core signature genes.
Fig. 5: Androgen regulates ER-to-Golgi vesicle-mediated trafficking in PCa through up-regulating the expression of core signature genes.
Fig. 6: ER-to-Golgi vesicle-mediated transport core signature genes are necessary for PCa cell survival and proliferation.
Fig. 7: CREB3L2 collaborates with AR to directly regulate the transcription of ER-to-Golgi vesicle coating components.

Data availability

All the sequencing data from this work have been submitted to the NCBI Gene Expression Omnibus (GEO) under accession numbers GSE145845 (scRNA-seq) and GSE165562 (ChIP-seq).

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Acknowledgements

We would like to thank Guimei Cui and Mi Chen for their help with the ChIP assay. We would also like to acknowledge the Animal Research Core, Bioimaging and Stem Cell Core, and Genomics, Bioinformatics & Single Cell Analysis Core at FHS. This work was performed in part at the High-Performance Computing Cluster (HPCC), which is supported by the Information and Communication Technology Office (ICTO) of the University of Macau. We thank Jacky Chan Hoi Kei and William Pang from HPCC for their support and help.

Funding

We are grateful for financial support from the National Science Foundation of China (Grant No. 62003094) to X.C., the University of Macau (MYRG2018-00033-FHS and MYRG2020-00100-FHS) and the Macau Science and Technology Development Fund (102/2015/A3, 0137/2020/A3, and 0011/2019/AKP) to E.C.

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Contributions

L.H. and E.C. conceived and designed the project; X.C., N.N., C.T., P.G., and Z.Z. conducted bioinformatics analysis with guidance from W.K.S. and E.C.; L.H., M.G.L.L., Z.C., U.I.C., and M.D. performed experiments under the supervision of X.X., W.K.S., and E.C.; L.H. and E.C. drafted the manuscript with inputs from all the authors.

Corresponding authors

Correspondence to Wing-Kin Sung or Edwin Cheung.

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Hu, L., Chen, X., Narwade, N. et al. Single-cell analysis reveals androgen receptor regulates the ER-to-Golgi trafficking pathway with CREB3L2 to drive prostate cancer progression. Oncogene (2021). https://doi.org/10.1038/s41388-021-02026-7

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