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The androgen receptor regulates a druggable translational regulon in advanced prostate cancer

Yuzhen Liu https://orcid.org/0000-0002-7299-4708, Jessie L. Horn https://orcid.org/0000-0003-2300-2781, Kalyan Banda https://orcid.org/0000-0003-2581-6906, Asha Z. Goodman, Yiting Lim, Sujata Jana https://orcid.org/0000-0003-2718-0307, Sonali Arora https://orcid.org/0000-0002-6661-3024, Alexandre A. Germanos https://orcid.org/0000-0003-4677-1313, Lexiaochuan Wen, William R. Hardin https://orcid.org/0000-0002-6328-9679, Yu C. Yang https://orcid.org/0000-0001-8318-1174, Ilsa M. Coleman, Robin G. Tharakan, Elise Y. Cai https://orcid.org/0000-0002-2697-2508, Takuma Uo, Smitha P. S. Pillai, Eva Corey https://orcid.org/0000-0002-9244-3807, Colm Morrissey https://orcid.org/0000-0003-1906-5333, Yu Chen, Brett S. Carver, Stephen R. Plymate, Slobodan Beronja, Peter S. Nelson, and Andrew C. Hsieh https://orcid.org/0000-0002-0897-1050 [email protected]
Science Translational Medicine • 31 Jul 2019 • Vol 11, Issue 503 • DOI: 10.1126/scitranslmed.aaw4993
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Druggable cancer phosphatases

Driving out translation to treat cancer

The androgen receptor is a well-known driver of prostate cancer and a common therapeutic target in this disease. Now, Liu et al. have identified an unexpected link between the androgen receptor and regulation of mRNA translation. The authors determined that the androgen receptor has a suppressive effect on protein synthesis, whereas the loss of this receptor is associated with increased initiation of translation, facilitating tumor cell proliferation. This observation helps explain the rapid growth of late-stage androgen receptor–deficient prostate cancer and provides a therapeutic opportunity through inhibition of a translation initiation complex, which the authors demonstrate in mouse models.

Abstract

The androgen receptor (AR) is a driver of cellular differentiation and prostate cancer development. An extensive body of work has linked these normal and aberrant cellular processes to mRNA transcription; however, the extent to which AR regulates posttranscriptional gene regulation remains unknown. Here, we demonstrate that AR uses the translation machinery to shape the cellular proteome. We show that AR is a negative regulator of protein synthesis and identify an unexpected relationship between AR and the process of translation initiation in vivo. This is mediated through direct transcriptional control of the translation inhibitor 4EBP1. We demonstrate that lowering AR abundance increases the assembly of the eIF4F translation initiation complex, which drives enhanced tumor cell proliferation. Furthermore, we uncover a network of pro-proliferation mRNAs characterized by a guanine-rich cis-regulatory element that is particularly sensitive to eIF4F hyperactivity. Using both genetic and pharmacologic methods, we demonstrate that dissociation of the eIF4F complex reverses the proliferation program, resulting in decreased tumor growth and improved survival in preclinical models. Our findings reveal a druggable nexus that functionally links the processes of mRNA transcription and translation initiation in an emerging class of lethal AR-deficient prostate cancer.
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Supplementary Material

Summary

Materials and Methods
Fig. S1. Castration of PtenL/L mice decreases AR, AR activity, and 4EBP1 without affecting eIF4F components.
Fig. S2. AR regulates 4ebp1 transcription but does not affect translation efficiency or degradation rates.
Fig. S3. Androgen deprivation is associated with decreased 4EBP1 expression; DHT add back decreases de novo protein synthesis.
Fig. S4. AR binds to an ARE in 4ebp1 in both normal and cancerous prostates, rendering 4EBP1 AR responsive.
Fig. S5. Castrate PtenL/L mice develop highly aggressive, nonneuroendocrine tumors independent of PI3K or MNK1/2 activity.
Fig. S6. AR/eIF4F-sensitive mRNAs are distinct from mTOR inhibition–sensitive mRNAs.
Fig. S7. Protein but not mRNA expression of GRTE-containing proliferation regulators is responsive to changes in eIF4F activity.
Fig. S8. Decreased eIF4F complex formation by 4EBP1M results in smaller and less aggressive tumors in castrate PtenL/L;4ebp1M mice.
Fig. S9. Castrate PtenL/L mice exhibit increased sensitivity to eIF4F disruption; 4EBP1 abundance is independent of AR in HSPC.
Fig. S10. 4E2RCat and 4EGI-1 disrupt eIF4F complex formation in PtenL/L cells, AR+ parental, and AR− APIPC cells.
Fig. S11. AR- and eIF4F-targeted combinatorial treatments in LNCaP prostate cancer cells demonstrate antitumor activity.
Fig. S12. AR shapes the prostate cancer proteome through 4EBP1 and a druggable pro-proliferation translational regulon.
Table S1. mRNA expression of AR signature genes comparing castrate PtenL/L ventral prostates to intact PtenL/L ventral prostates.
Table S2. Position-weighted map of the 5′UTR GRTE.
Table S3. Primers used in this study.
Data file S1. Translationally up-regulated genes in the castrate PtenL/L mouse.
Data file S2. Tumor measurements from in vivo experiments.
References (45–47)

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Science Translational Medicine
Volume 11 | Issue 503
July 2019

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Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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Received: 1 January 2019
Accepted: 24 June 2019

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Acknowledgments

We are grateful to the patients who participated in this study and their families. We thank members of the A.C.H. laboratory for helpful advice. We thank J. M. Shen for editing the manuscript. We thank A. Geballe, A. Subramaniam, C. Ghajar, and C. Bellodi for critical discussion of the paper. We thank L. Xin for providing ChIP-seq and RNA-seq data from wild-type murine prostate luminal epithelial cells. We thank S. Kugel for providing Riptag2 neuroendocrine cells. Funding: This work was supported by NIH award 1R37CA230617, the Pacific Northwest Prostate Cancer SPORE (P50CA097186, P01CA163227, and CA182503-01A1), the CDMRP (W81XWH-17-1-0415), and the Shared Resources of FHCRC/UW Cancer Consortium (P30 CA015704). A.C.H. is a V Foundation Scholar and is funded by a NextGen Grant for Transformative Cancer Research from the American Association for Cancer Research (AACR) and a Burroughs Wellcome Fund Career Award for Medical Scientists. K.B. is a recipient of an American Society of Clinical Oncology Endowed Young Investigator Award in memory of S. Gordon, a National Cancer Institute training grant (T32CA009515), and a Pilot and Feasibility Studies Program grant funded by the Cooperative Center for Excellence in Hematology (U54 DK106829). Y. Lim received funding through a Department of Defense Prostate Cancer Research Program Postdoctoral Training Award (PC150946) and the AACR. A.C.H., Y.C., and B.S.C. are funded by a Movember-Prostate Cancer Foundation Challenge Award. Author contributions: A.C.H. conceived the project; Y. Liu, J.L.H., K.B., and A.Z.G., performed mouse experiments; Y. Liu., J.L.H., A.A.G., L.W., W.R.H., and K.B. conducted molecular and cell biology experiments; Y. Lim conducted the ribosome profiling experiment; S.J. conducted the in vitro proximity ligation assay; R.G.T., Y.C.Y., I.M.C., and P.S.N. assisted with the RNA-seq experiment; Y.C. conducted the ChIP-seq analysis; E.Y.C. and S.B. assisted with shRNA experiments; B.S.C. assisted with enzalutamide experiments; A.A.G. conducted the 5′UTR studies; S.A. conducted computational analysis; T.U. and S.R.P. assisted with ARE experiments; S.P.S.P. conducted blinded pathology evaluation; E.C. and C.M. provided biospecimens and AR staining in the human studies; A.C.H. wrote the manuscript with input from Y. Liu, J.L.H., K.B., Y. Lim, S.J., and A.A.G.; all authors reviewed and edited the manuscript. Competing interests: A.C.H. receives research funding from eFFECTOR Inc. P.S.N. has consulted for Janssen and Astellas Pharma Inc. All other authors declare that they have no competing interests. Data and materials availability: Raw RNA-seq and ribosome profiling sequencing data can be accessed at Sequence Read Archive (SRP151005 and SRP151006) and NCBI Gene Expression Omnibus (GSE116081 and GSE116082). Raw ChIP-seq data from PtenL/L prostates were obtained from Gene Expression Omnibus (GSE47119). All other data associated with this study are present in the paper or the Supplementary Materials.

Authors

Affiliations

Yuzhen Liu* https://orcid.org/0000-0002-7299-4708
Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
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Jessie L. Horn* https://orcid.org/0000-0003-2300-2781
Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
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Kalyan Banda* https://orcid.org/0000-0003-2581-6906
Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
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Asha Z. Goodman
Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
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Yiting Lim
Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
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Sujata Jana https://orcid.org/0000-0003-2718-0307
Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
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Sonali Arora https://orcid.org/0000-0002-6661-3024
Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
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Alexandre A. Germanos https://orcid.org/0000-0003-4677-1313
Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
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Lexiaochuan Wen
Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
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William R. Hardin https://orcid.org/0000-0002-6328-9679
Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
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Yu C. Yang https://orcid.org/0000-0001-8318-1174
Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
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Ilsa M. Coleman
Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
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Robin G. Tharakan
Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
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Elise Y. Cai https://orcid.org/0000-0002-2697-2508
Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
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Takuma Uo
Department of Medicine, Division of Gerontology and Geriatric Medicine, University of Washington, Seattle, WA 98104, USA.
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Smitha P. S. Pillai
Comparative Medicine, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
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Eva Corey https://orcid.org/0000-0002-9244-3807
Department of Urology, University of Washington, Seattle, WA 98915, USA.
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Colm Morrissey https://orcid.org/0000-0003-1906-5333
Department of Urology, University of Washington, Seattle, WA 98915, USA.
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Yu Chen
Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
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Brett S. Carver
Department of Urology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
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Stephen R. Plymate
Department of Medicine, Division of Gerontology and Geriatric Medicine, University of Washington, Seattle, WA 98104, USA.
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Slobodan Beronja
Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
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Peter S. Nelson
Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Departments of Medicine and Genome Sciences, University of Washington, Seattle, WA 98195, USA.
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Andrew C. Hsieh† https://orcid.org/0000-0002-0897-1050 [email protected]
Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Departments of Medicine and Genome Sciences, University of Washington, Seattle, WA 98195, USA.
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Funding Information

Notes

*
These authors contributed equally to this work.
†Corresponding author. Email: [email protected]

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