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Increased AR expression in castration-resistant prostate cancer rapidly induces AR signaling reprogramming with the collaboration of EZH2

Elevated androgen receptor (AR) expression is a hallmark of castration-resistant prostate cancer (CRPC) and contributes to the restoration of AR signaling under the conditions of androgen deprivation. However, whether overexpressed AR alone with the stimulation of castrate levels of androgens can be...

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Autores principales: Labaf, Maryam, Li, Muqing, Ting, Lily, Karno, Breelyn, Zhang, Songqi, Gao, Shuai, Patalano, Susan, Macoska, Jill A., Zarringhalam, Kourosh, Han, Dong, Cai, Changmeng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9669968/
https://www.ncbi.nlm.nih.gov/pubmed/36408179
http://dx.doi.org/10.3389/fonc.2022.1021845
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author Labaf, Maryam
Li, Muqing
Ting, Lily
Karno, Breelyn
Zhang, Songqi
Gao, Shuai
Patalano, Susan
Macoska, Jill A.
Zarringhalam, Kourosh
Han, Dong
Cai, Changmeng
author_facet Labaf, Maryam
Li, Muqing
Ting, Lily
Karno, Breelyn
Zhang, Songqi
Gao, Shuai
Patalano, Susan
Macoska, Jill A.
Zarringhalam, Kourosh
Han, Dong
Cai, Changmeng
author_sort Labaf, Maryam
collection PubMed
description Elevated androgen receptor (AR) expression is a hallmark of castration-resistant prostate cancer (CRPC) and contributes to the restoration of AR signaling under the conditions of androgen deprivation. However, whether overexpressed AR alone with the stimulation of castrate levels of androgens can be sufficient to induce the reprogramming of AR signaling for the adaptation of prostate cancer (PCa) cells remains unclear. In this study, we used a PCa model with inducible overexpression of AR to examine the acute effects of AR overexpression on its cistrome and transcriptome. Our results show that overexpression of AR alone in conjunction with lower androgen levels can rapidly redistribute AR chromatin binding and activates a distinct transcription program that is enriched for DNA damage repair pathways. Moreover, using a recently developed bioinformatic tool, we predicted the involvement of EZH2 in this AR reprogramming and subsequently identified a subset of AR/EZH2 co-targeting genes, which are overexpressed in CRPC and associated with worse patient outcomes. Mechanistically, we found that AR-EZH2 interaction is impaired by the pre-castration level of androgens but can be recovered by the post-castration level of androgens. Overall, our study provides new molecular insights into AR signaling reprogramming with the engagement of specific epigenetic factors.
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spelling pubmed-96699682022-11-18 Increased AR expression in castration-resistant prostate cancer rapidly induces AR signaling reprogramming with the collaboration of EZH2 Labaf, Maryam Li, Muqing Ting, Lily Karno, Breelyn Zhang, Songqi Gao, Shuai Patalano, Susan Macoska, Jill A. Zarringhalam, Kourosh Han, Dong Cai, Changmeng Front Oncol Oncology Elevated androgen receptor (AR) expression is a hallmark of castration-resistant prostate cancer (CRPC) and contributes to the restoration of AR signaling under the conditions of androgen deprivation. However, whether overexpressed AR alone with the stimulation of castrate levels of androgens can be sufficient to induce the reprogramming of AR signaling for the adaptation of prostate cancer (PCa) cells remains unclear. In this study, we used a PCa model with inducible overexpression of AR to examine the acute effects of AR overexpression on its cistrome and transcriptome. Our results show that overexpression of AR alone in conjunction with lower androgen levels can rapidly redistribute AR chromatin binding and activates a distinct transcription program that is enriched for DNA damage repair pathways. Moreover, using a recently developed bioinformatic tool, we predicted the involvement of EZH2 in this AR reprogramming and subsequently identified a subset of AR/EZH2 co-targeting genes, which are overexpressed in CRPC and associated with worse patient outcomes. Mechanistically, we found that AR-EZH2 interaction is impaired by the pre-castration level of androgens but can be recovered by the post-castration level of androgens. Overall, our study provides new molecular insights into AR signaling reprogramming with the engagement of specific epigenetic factors. Frontiers Media S.A. 2022-11-03 /pmc/articles/PMC9669968/ /pubmed/36408179 http://dx.doi.org/10.3389/fonc.2022.1021845 Text en Copyright © 2022 Labaf, Li, Ting, Karno, Zhang, Gao, Patalano, Macoska, Zarringhalam, Han and Cai https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Labaf, Maryam
Li, Muqing
Ting, Lily
Karno, Breelyn
Zhang, Songqi
Gao, Shuai
Patalano, Susan
Macoska, Jill A.
Zarringhalam, Kourosh
Han, Dong
Cai, Changmeng
Increased AR expression in castration-resistant prostate cancer rapidly induces AR signaling reprogramming with the collaboration of EZH2
title Increased AR expression in castration-resistant prostate cancer rapidly induces AR signaling reprogramming with the collaboration of EZH2
title_full Increased AR expression in castration-resistant prostate cancer rapidly induces AR signaling reprogramming with the collaboration of EZH2
title_fullStr Increased AR expression in castration-resistant prostate cancer rapidly induces AR signaling reprogramming with the collaboration of EZH2
title_full_unstemmed Increased AR expression in castration-resistant prostate cancer rapidly induces AR signaling reprogramming with the collaboration of EZH2
title_short Increased AR expression in castration-resistant prostate cancer rapidly induces AR signaling reprogramming with the collaboration of EZH2
title_sort increased ar expression in castration-resistant prostate cancer rapidly induces ar signaling reprogramming with the collaboration of ezh2
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9669968/
https://www.ncbi.nlm.nih.gov/pubmed/36408179
http://dx.doi.org/10.3389/fonc.2022.1021845
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