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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...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
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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. |
format | Online Article Text |
id | pubmed-9669968 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
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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