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Nuclear βArrestin1 regulates androgen receptor function in castration resistant prostate cancer

Oncogene volume 40, pages 2610–2620 (2021)Cite this article

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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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Fig. 1: βArr1 regulates AR transcription.
Fig. 2: βArr1 regulates AR through βCat.
Fig. 3: βArr1 forms complex with AR and βCat.
Fig. 4: βArr1 functions as AR co-activator.
Fig. 5: Nuclear βArr1 promotes prostate tumor growth and metastasis.

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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.

References

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70:7–30.

    Article  Google Scholar 

  2. Claessens F, Helsen C, Prekovic S, Van den Broeck T, Spans L, Van Poppel H, et al. Emerging mechanisms of enzalutamide resistance in prostate cancer. Nat Rev Urol. 2014;11:712–6.

    Article  CAS  PubMed  Google Scholar 

  3. Watson PA, Arora VK, Sawyers CL. Emerging mechanisms of resistance to androgen receptor inhibitors in prostate cancer. Nat Rev Cancer. 2015;15:701–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Taplin ME. Drug insight: role of the androgen receptor in the development and progression of prostate cancer. Nat Clin Pr Oncol. 2007;4:236–44.

    Article  CAS  Google Scholar 

  5. Dehm SM, Tindall DJ. Alternatively spliced androgen receptor variants. Endocr Relat Cancer. 2011;18:R183–196.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Titus MA, Schell MJ, Lih FB, Tomer KB, Mohler JL. Testosterone and dihydrotestosterone tissue levels in recurrent prostate cancer. Clin Cancer Res. 2005;11:4653–7.

    Article  CAS  PubMed  Google Scholar 

  7. Heemers HV, Tindall DJ. Androgen receptor (AR) coregulators: a diversity of functions converging on and regulating the AR transcriptional complex. Endocr Rev. 2007;28:778–808.

    Article  CAS  PubMed  Google Scholar 

  8. Beltran H, Hruszkewycz A, Scher HI, Hildesheim J, Isaacs J, Yu EY, et al. The role of lineage plasticity in prostate cancer therapy resistance. Clin Cancer Res. 2019;25:6916–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Ku SY, Rosario S, Wang Y, Mu P, Seshadri M, Goodrich ZW, et al. Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance. Science. 2017;355:78–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Mu P, Zhang Z, Benelli M, Karthaus WR, Hoover E, Chen CC, et al. SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer. Science. 2017;355:84–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Arora VK, Schenkein E, Murali R, Subudhi SK, Wongvipat J, Balbas MD, et al. Glucocorticoid receptor confers resistance to antiandrogens by bypassing androgen receptor blockade. Cell. 2013;155:1309–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Lee E, Madar A, David G, Garabedian MJ, Dasgupta R, Logan SK. Inhibition of androgen receptor and beta-catenin activity in prostate cancer. Proc Natl Acad Sci USA. 2013;110:15710–5.

    Article  CAS  PubMed  Google Scholar 

  13. Mulholland DJ, Cheng H, Reid K, Rennie PS, Nelson CC. The androgen receptor can promote beta-catenin nuclear translocation independently of adenomatous polyposis coli. J Biol Chem. 2002;277:17933–43.

    Article  CAS  PubMed  Google Scholar 

  14. Lefkowitz RJ. Historical review: a brief history and personal retrospective of seven-transmembrane receptors. Trends Pharm Sci. 2004;25:413–22.

    Article  CAS  PubMed  Google Scholar 

  15. Benovic JL, Kuhn H, Weyand I, Codina J, Caron MG, Lefkowitz RJ. Functional desensitization of the isolated beta-adrenergic receptor by the beta-adrenergic receptor kinase: potential role of an analog of the retinal protein arrestin (48-kDa protein). Proc Natl Acad Sci USA. 1987;84:8879–82.

    Article  CAS  PubMed  Google Scholar 

  16. Purayil HT, Zhang Y, Dey A, Gersey Z, Espana-Serrano L, Daaka Y. Arrestin2 modulates androgen receptor activation. Oncogene. 2015;34:3144–51.

    Article  CAS  PubMed  Google Scholar 

  17. Rosano L, Cianfrocca R, Masi S, Spinella F, Di Castro V, Biroccio A, et al. Beta-arrestin links endothelin A receptor to beta-catenin signaling to induce ovarian cancer cell invasion and metastasis. Proc Natl Acad Sci USA. 2009;106:2806–11.

    Article  CAS  PubMed  Google Scholar 

  18. Zecchini V, Madhu B, Russell R, Pertega-Gomes N, Warren A, Gaude E, et al. Nuclear ARRB1 induces pseudohypoxia and cellular metabolism reprogramming in prostate cancer. EMBO J. 2014;33:1365–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Luttrell LM, Ferguson SS, Daaka Y, Miller WE, Maudsley S, Della Rocca GJ, et al. Beta-arrestin-dependent formation of beta2 adrenergic receptor-Src protein kinase complexes. Science. 1999;283:655–61.

    Article  CAS  PubMed  Google Scholar 

  20. Wang LG, Su BH, Du JJ. Expression of beta-arrestin 1 in gastric cardiac adenocarcinoma and its relation with progression. Asian Pac J Cancer Prev. 2012;13:5671–5.

    Article  PubMed  Google Scholar 

  21. Buchanan FG, Gorden DL, Matta P, Shi Q, Matrisian LM, DuBois RN. Role of beta-arrestin 1 in the metastatic progression of colorectal cancer. Proc Natl Acad Sci USA. 2006;103:1492–7.

    Article  CAS  PubMed  Google Scholar 

  22. El-Khoury V, Beland M, Schritz A, Kim SY, Nazarov PV, Gaboury L, et al. Identification of beta-arrestin-1 as a diagnostic biomarker in lung cancer. Br J Cancer. 2018;119:580–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Zhang YX, Li XF, Yuan GQ, Hu H, Song XY, Li JY, et al. beta-Arrestin 1 has an essential role in neurokinin-1 receptor-mediated glioblastoma cell proliferation and G2/M phase transition. J Biol Chem. 2017;292:8933–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Masannat J, Purayil HT, Zhang Y, Russin M, Mahmud I, Kim W, et al. betaArrestin2 Mediates Renal Cell Carcinoma Tumor Growth. Sci Rep. 2018;8:4879.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Fereshteh M, Ito T, Kovacs JJ, Zhao C, Kwon HY, Tornini V, et al. beta-Arrestin2 mediates the initiation and progression of myeloid leukemia. Proc Natl Acad Sci USA. 2012;109:12532–7.

    Article  CAS  PubMed  Google Scholar 

  26. Hirsch JA, Schubert C, Gurevich VV, Sigler PB. The 2.8 A crystal structure of visual arrestin: a model for arrestin’s regulation. Cell. 1999;97:257–69.

    Article  CAS  PubMed  Google Scholar 

  27. Ma L, Pei G. Beta-arrestin signaling and regulation of transcription. J Cell Sci. 2007;120:213–8.

    Article  CAS  PubMed  Google Scholar 

  28. Scott MG, Le Rouzic E, Perianin A, Pierotti V, Enslen H, Benichou S, et al. Differential nucleocytoplasmic shuttling of beta-arrestins. Characterization of a leucine-rich nuclear export signal in beta-arrestin2. J Biol Chem. 2002;277:37693–701.

    Article  CAS  PubMed  Google Scholar 

  29. Kang J, Shi Y, Xiang B, Qu B, Su W, Zhu M, et al. A nuclear function of beta-arrestin1 in GPCR signaling: regulation of histone acetylation and gene transcription. Cell. 2005;123:833–47.

    Article  CAS  PubMed  Google Scholar 

  30. Dasgupta P, Rizwani W, Pillai S, Davis R, Banerjee S, Hug K, et al. ARRB1-mediated regulation of E2F target genes in nicotine-induced growth of lung tumors. J Natl Cancer Inst. 2011;103:317–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Rosano L, Cianfrocca R, Tocci P, Spinella F, Di Castro V, Spadaro F, et al. beta-arrestin-1 is a nuclear transcriptional regulator of endothelin-1-induced beta-catenin signaling. Oncogene. 2013;32:5066–77.

    Article  CAS  PubMed  Google Scholar 

  32. Cianfrocca R, Tocci P, Semprucci E, Spinella F, Di Castro V, Bagnato A, et al. beta-Arrestin 1 is required for endothelin-1-induced NF-kappaB activation in ovarian cancer cells. Life Sci. 2014;118:179–84.

    Article  CAS  PubMed  Google Scholar 

  33. Tocci P, Cianfrocca R, Di Castro V, Rosano L, Sacconi A, Donzelli S, et al. beta-arrestin1/YAP/mutant p53 complexes orchestrate the endothelin A receptor signaling in high-grade serous ovarian cancer. Nat Commun. 2019;10:3196.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Shenoy SK, Han S, Zhao YL, Hara MR, Oliver T, Cao Y, et al. beta-arrestin1 mediates metastatic growth of breast cancer cells by facilitating HIF-1-dependent VEGF expression. Oncogene. 2012;31:282–92.

    Article  CAS  PubMed  Google Scholar 

  35. Cancer Genome Atlas Research N. The molecular taxonomy of primary prostate cancer. Cell. 2015;163:1011–25.

    Article  Google Scholar 

  36. Terada N, Shimizu Y, Kamba T, Inoue T, Maeno A, Kobayashi T, et al. Identification of EP4 as a potential target for the treatment of castration-resistant prostate cancer using a novel xenograft model. Cancer Res. 2010;70:1606–15.

    Article  CAS  PubMed  Google Scholar 

  37. Bao BY, Chuang BF, Wang Q, Sartor O, Balk SP, Brown M, et al. Androgen receptor mediates the expression of UDP-glucuronosyltransferase 2 B15 and B17 genes. Prostate. 2008;68:839–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Xiao K, McClatchy DB, Shukla AK, Zhao Y, Chen M, Shenoy SK, et al. Functional specialization of beta-arrestin interactions revealed by proteomic analysis. Proc Natl Acad Sci USA. 2007;104:12011–6.

    Article  CAS  PubMed  Google Scholar 

  39. Wang P, Wu Y, Ge X, Ma L, Pei G. Subcellular localization of beta-arrestins is determined by their intact N domain and the nuclear export signal at the C terminus. J Biol Chem. 2003;278:11648–53.

    Article  CAS  PubMed  Google Scholar 

  40. Nyquist MD, Li Y, Hwang TH, Manlove LS, Vessella RL, Silverstein KA, et al. TALEN-engineered AR gene rearrangements reveal endocrine uncoupling of androgen receptor in prostate cancer. Proc Natl Acad Sci USA. 2013;110:17492–7.

    Article  CAS  PubMed  Google Scholar 

  41. Lakshmikanthan V, Zou L, Kim JI, Michal A, Nie Z, Messias NC, et al. Identification of betaArrestin2 as a corepressor of androgen receptor signaling in prostate cancer. Proc Natl Acad Sci USA. 2009;106:9379–84.

    Article  CAS  PubMed  Google Scholar 

  42. Zhang Y, Thayele Purayil H, Black JB, Fetto F, Lynch LD, Masannat JN, et al. Prostaglandin E2 receptor 4 mediates renal cell carcinoma intravasation and metastasis. Cancer Lett. 2017;391:50–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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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.

Funding

This work was supported, in part, by the Florida Academic Cancer Center Alliance (to YD) and the UFHCC (to RG).

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Author notes

  1. Yushan Zhang

    Present address: Stephen Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma, OK, USA

Authors and Affiliations

  1. Department of Anatomy and Cell Biology, College of Medicine, University of Florida, Gainesville, FL, USA

    Hamsa Thayele Purayil, Yushan Zhang, Joseph B. Black & Yehia Daaka

  2. Department of Medicine, College of Medicine, University of Florida, Gainesville, FL, USA

    Raad Gharaibeh

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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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Correspondence to Yehia Daaka.

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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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