Proteostasis by STUB1/HSP70 complex controls sensitivity to androgen receptor targeted therapy in advanced prostate cancer

Protein homeostasis (proteostasis) is a potential mechanism that contributes to cancer cell survival and drug resistance. Constitutively active androgen receptor (AR) variants confer anti-androgen resistance in advanced prostate cancer. However, the role of proteostasis involved in next generation a...

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Autores principales: Liu, Chengfei, Lou, Wei, Yang, Joy C., Liu, Liangren, Armstrong, Cameron M., Lombard, Alan P., Zhao, Ruining, Noel, Onika D. V., Tepper, Clifford G., Chen, Hong-Wu, Dall’Era, Marc, Evans, Christopher P., Gao, Allen C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
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Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6240084/
https://www.ncbi.nlm.nih.gov/pubmed/30446660
http://dx.doi.org/10.1038/s41467-018-07178-x
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author Liu, Chengfei
Lou, Wei
Yang, Joy C.
Liu, Liangren
Armstrong, Cameron M.
Lombard, Alan P.
Zhao, Ruining
Noel, Onika D. V.
Tepper, Clifford G.
Chen, Hong-Wu
Dall’Era, Marc
Evans, Christopher P.
Gao, Allen C.
author_facet Liu, Chengfei
Lou, Wei
Yang, Joy C.
Liu, Liangren
Armstrong, Cameron M.
Lombard, Alan P.
Zhao, Ruining
Noel, Onika D. V.
Tepper, Clifford G.
Chen, Hong-Wu
Dall’Era, Marc
Evans, Christopher P.
Gao, Allen C.
author_sort Liu, Chengfei
collection PubMed
description Protein homeostasis (proteostasis) is a potential mechanism that contributes to cancer cell survival and drug resistance. Constitutively active androgen receptor (AR) variants confer anti-androgen resistance in advanced prostate cancer. However, the role of proteostasis involved in next generation anti-androgen resistance and the mechanisms of AR variant regulation are poorly defined. Here we show that the ubiquitin-proteasome-system (UPS) is suppressed in enzalutamide/abiraterone resistant prostate cancer. AR/AR-V7 proteostasis requires the interaction of E3 ubiquitin ligase STUB1 and HSP70 complex. STUB1 disassociates AR/AR-V7 from HSP70, leading to AR/AR-V7 ubiquitination and degradation. Inhibition of HSP70 significantly inhibits prostate tumor growth and improves enzalutamide/abiraterone treatments through AR/AR-V7 suppression. Clinically, HSP70 expression is upregulated and correlated with AR/AR-V7 levels in high Gleason score prostate tumors. Our results reveal a novel mechanism of anti-androgen resistance via UPS alteration which could be targeted through inhibition of HSP70 to reduce AR-V7 expression and overcome resistance to AR-targeted therapies.
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spelling pubmed-62400842018-11-19 Proteostasis by STUB1/HSP70 complex controls sensitivity to androgen receptor targeted therapy in advanced prostate cancer Liu, Chengfei Lou, Wei Yang, Joy C. Liu, Liangren Armstrong, Cameron M. Lombard, Alan P. Zhao, Ruining Noel, Onika D. V. Tepper, Clifford G. Chen, Hong-Wu Dall’Era, Marc Evans, Christopher P. Gao, Allen C. Nat Commun Article Protein homeostasis (proteostasis) is a potential mechanism that contributes to cancer cell survival and drug resistance. Constitutively active androgen receptor (AR) variants confer anti-androgen resistance in advanced prostate cancer. However, the role of proteostasis involved in next generation anti-androgen resistance and the mechanisms of AR variant regulation are poorly defined. Here we show that the ubiquitin-proteasome-system (UPS) is suppressed in enzalutamide/abiraterone resistant prostate cancer. AR/AR-V7 proteostasis requires the interaction of E3 ubiquitin ligase STUB1 and HSP70 complex. STUB1 disassociates AR/AR-V7 from HSP70, leading to AR/AR-V7 ubiquitination and degradation. Inhibition of HSP70 significantly inhibits prostate tumor growth and improves enzalutamide/abiraterone treatments through AR/AR-V7 suppression. Clinically, HSP70 expression is upregulated and correlated with AR/AR-V7 levels in high Gleason score prostate tumors. Our results reveal a novel mechanism of anti-androgen resistance via UPS alteration which could be targeted through inhibition of HSP70 to reduce AR-V7 expression and overcome resistance to AR-targeted therapies. Nature Publishing Group UK 2018-11-16 /pmc/articles/PMC6240084/ /pubmed/30446660 http://dx.doi.org/10.1038/s41467-018-07178-x Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Liu, Chengfei
Lou, Wei
Yang, Joy C.
Liu, Liangren
Armstrong, Cameron M.
Lombard, Alan P.
Zhao, Ruining
Noel, Onika D. V.
Tepper, Clifford G.
Chen, Hong-Wu
Dall’Era, Marc
Evans, Christopher P.
Gao, Allen C.
Proteostasis by STUB1/HSP70 complex controls sensitivity to androgen receptor targeted therapy in advanced prostate cancer
title Proteostasis by STUB1/HSP70 complex controls sensitivity to androgen receptor targeted therapy in advanced prostate cancer
title_full Proteostasis by STUB1/HSP70 complex controls sensitivity to androgen receptor targeted therapy in advanced prostate cancer
title_fullStr Proteostasis by STUB1/HSP70 complex controls sensitivity to androgen receptor targeted therapy in advanced prostate cancer
title_full_unstemmed Proteostasis by STUB1/HSP70 complex controls sensitivity to androgen receptor targeted therapy in advanced prostate cancer
title_short Proteostasis by STUB1/HSP70 complex controls sensitivity to androgen receptor targeted therapy in advanced prostate cancer
title_sort proteostasis by stub1/hsp70 complex controls sensitivity to androgen receptor targeted therapy in advanced prostate cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6240084/
https://www.ncbi.nlm.nih.gov/pubmed/30446660
http://dx.doi.org/10.1038/s41467-018-07178-x
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