Abstract
Progression of prostate cancer (PC) to terminal castration-resistant PC (CRPC) involves a diverse set of intermediates, and androgen receptor (AR) is the key mediator of PC initiation and progression to CRPC. Hence, identification of factors involved in the regulation of AR expression and function is a necessary first-step to improve disease outcome. In this study, we identified ubiquitous βArrestin 1 (βArr1) as a regulator of AR function in CRPC. Unbiased gene expression analysis of public datasets revealed increased levels of ARRB1 (the gene encoding βArr1) in CRPC when compared to normal tissue. Further, βArr1 expression correlated with enhanced AR transcriptional function in these datasets. The βArr1 partitions to both nucleus and cytosol and mechanistic studies showed that nuclear, and not cytosolic, βArr1 formed a complex with AR and AR-coregulator βCatenin and that the heterotrimeric protein complex was recruited to androgen-response elements of AR-regulated genes. Functionally, we demonstrate that depletion of βArr1 attenuates PC cell and tumor growth and metastasis, and rescued expression of nuclear, but not cytosolic, βArr1 restores the PC colony growth and invasion of Matrigel in vitro and tumor growth and metastasis in mice. The targeting of βArr1-regulated AR transcriptional function may be used in the development of new drugs to treat lethal CRPC.
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Data availability
All data associated with this study are present in the paper or in the Supplementary Materials. The RNA-seq data that support the findings of this study have been deposited in the GEO repository with accession code GSE165168.
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Acknowledgements
We thank Dr. Vincent Zecchini (University of Cambridge, Cambridge, UK) for kindly providing a plasmid encoding humanized βArr1, Dr. Mark A. Wallet (University of Florida, Florida, USA) for help with virus purification, and Dr. Scott M. Dehm (University of Minnesota, Minnesota, USA) for providing AR engineered CWR cells lines. We thank Drs. Ranjan Perera (Johns Hopkins All Children Hospital, Florida, USA) and Subramaniam Govindaraian (Guandrant Health, California, USA) for RNA sequencing.
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This work was supported, in part, by the Florida Academic Cancer Center Alliance (to YD) and the UFHCC (to RG).
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HTP and YD designed the research. HTP, YZ, and JBB performed experiments. HTP and RG analyzed the RNA-seq data. All authors interpreted the data. HTP and YD wrote the paper that was approved by all authors.
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Purayil, H.T., Zhang, Y., Black, J.B. et al. Nuclear βArrestin1 regulates androgen receptor function in castration resistant prostate cancer. Oncogene 40, 2610–2620 (2021). https://doi.org/10.1038/s41388-021-01730-8
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DOI: https://doi.org/10.1038/s41388-021-01730-8