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LncRNA PCAT1 activates AKT and NF-κB signaling in castration-resistant prostate cancer by regulating the PHLPP/FKBP51/IKKα complex

In PTEN-deficient prostate cancers, AKT signaling may be activated upon suppression of androgen receptor signaling. Activation of AKT as well as NF-κB signaling involves a key regulatory protein complex containing PHLPP, FKBP51 and IKKα. Here, we report a critical role of lncRNA PCAT1 in regulating...

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Autores principales: Shang, Zhiqun, Yu, Jianpeng, Sun, Libin, Tian, Jing, Zhu, Shimiao, Zhang, Boya, Dong, Qian, Jiang, Ning, Flores-Morales, Amilcar, Chang, Chawnshang, Niu, Yuanjie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6486551/
https://www.ncbi.nlm.nih.gov/pubmed/30773595
http://dx.doi.org/10.1093/nar/gkz108
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author Shang, Zhiqun
Yu, Jianpeng
Sun, Libin
Tian, Jing
Zhu, Shimiao
Zhang, Boya
Dong, Qian
Jiang, Ning
Flores-Morales, Amilcar
Chang, Chawnshang
Niu, Yuanjie
author_facet Shang, Zhiqun
Yu, Jianpeng
Sun, Libin
Tian, Jing
Zhu, Shimiao
Zhang, Boya
Dong, Qian
Jiang, Ning
Flores-Morales, Amilcar
Chang, Chawnshang
Niu, Yuanjie
author_sort Shang, Zhiqun
collection PubMed
description In PTEN-deficient prostate cancers, AKT signaling may be activated upon suppression of androgen receptor signaling. Activation of AKT as well as NF-κB signaling involves a key regulatory protein complex containing PHLPP, FKBP51 and IKKα. Here, we report a critical role of lncRNA PCAT1 in regulating the PHLPP/FKBP51/IKKα complex and progression of castration-resistant prostate cancer (CRPC). Using database queries, bioinformatic analyses, as well as RIP and RNA pull-down assays, we discovered and validated that the lncRNA-PCAT1 perturbs the PHLPP/FKBP51/IKKα complex and activates AKT and NF-κB signaling. Expression of lncRNA-PCAT1 is positively linked to CRPC progression. PCAT1 binds directly to FKBP51, displacing PHLPP from the PHLPP/FKBP51/IKKα complex, leading to activation of AKT and NF-κB signaling. Targeting PCAT1 restores PHLPP binding to FKBP1 leading to suppression of AKT signaling. Preclinical study in a mouse model of CRPC suggests therapeutic potential by targeting lncRNA PCAT1 to suppress CRPC progression. Together, the newly identified PCAT1/FKBP51/IKKα complex provides mechanistic insight in the interplay between AKT, NF-κB and AR signaling in CRPC, and the preclinical studies suggest that a novel role for PCAT1 as a therapeutic target.
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spelling pubmed-64865512019-05-01 LncRNA PCAT1 activates AKT and NF-κB signaling in castration-resistant prostate cancer by regulating the PHLPP/FKBP51/IKKα complex Shang, Zhiqun Yu, Jianpeng Sun, Libin Tian, Jing Zhu, Shimiao Zhang, Boya Dong, Qian Jiang, Ning Flores-Morales, Amilcar Chang, Chawnshang Niu, Yuanjie Nucleic Acids Res RNA and RNA-protein complexes In PTEN-deficient prostate cancers, AKT signaling may be activated upon suppression of androgen receptor signaling. Activation of AKT as well as NF-κB signaling involves a key regulatory protein complex containing PHLPP, FKBP51 and IKKα. Here, we report a critical role of lncRNA PCAT1 in regulating the PHLPP/FKBP51/IKKα complex and progression of castration-resistant prostate cancer (CRPC). Using database queries, bioinformatic analyses, as well as RIP and RNA pull-down assays, we discovered and validated that the lncRNA-PCAT1 perturbs the PHLPP/FKBP51/IKKα complex and activates AKT and NF-κB signaling. Expression of lncRNA-PCAT1 is positively linked to CRPC progression. PCAT1 binds directly to FKBP51, displacing PHLPP from the PHLPP/FKBP51/IKKα complex, leading to activation of AKT and NF-κB signaling. Targeting PCAT1 restores PHLPP binding to FKBP1 leading to suppression of AKT signaling. Preclinical study in a mouse model of CRPC suggests therapeutic potential by targeting lncRNA PCAT1 to suppress CRPC progression. Together, the newly identified PCAT1/FKBP51/IKKα complex provides mechanistic insight in the interplay between AKT, NF-κB and AR signaling in CRPC, and the preclinical studies suggest that a novel role for PCAT1 as a therapeutic target. Oxford University Press 2019-05-07 2019-02-18 /pmc/articles/PMC6486551/ /pubmed/30773595 http://dx.doi.org/10.1093/nar/gkz108 Text en © The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle RNA and RNA-protein complexes
Shang, Zhiqun
Yu, Jianpeng
Sun, Libin
Tian, Jing
Zhu, Shimiao
Zhang, Boya
Dong, Qian
Jiang, Ning
Flores-Morales, Amilcar
Chang, Chawnshang
Niu, Yuanjie
LncRNA PCAT1 activates AKT and NF-κB signaling in castration-resistant prostate cancer by regulating the PHLPP/FKBP51/IKKα complex
title LncRNA PCAT1 activates AKT and NF-κB signaling in castration-resistant prostate cancer by regulating the PHLPP/FKBP51/IKKα complex
title_full LncRNA PCAT1 activates AKT and NF-κB signaling in castration-resistant prostate cancer by regulating the PHLPP/FKBP51/IKKα complex
title_fullStr LncRNA PCAT1 activates AKT and NF-κB signaling in castration-resistant prostate cancer by regulating the PHLPP/FKBP51/IKKα complex
title_full_unstemmed LncRNA PCAT1 activates AKT and NF-κB signaling in castration-resistant prostate cancer by regulating the PHLPP/FKBP51/IKKα complex
title_short LncRNA PCAT1 activates AKT and NF-κB signaling in castration-resistant prostate cancer by regulating the PHLPP/FKBP51/IKKα complex
title_sort lncrna pcat1 activates akt and nf-κb signaling in castration-resistant prostate cancer by regulating the phlpp/fkbp51/ikkα complex
topic RNA and RNA-protein complexes
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6486551/
https://www.ncbi.nlm.nih.gov/pubmed/30773595
http://dx.doi.org/10.1093/nar/gkz108
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