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Androgen deprivation induces neuroendocrine phenotypes in prostate cancer cells through CREB1/EZH2-mediated downregulation of REST
Although effective initially, prolonged androgen deprivation therapy (ADT) promotes neuroendocrine differentiation (NED) and prostate cancer (PCa) progression. It is incompletely understood how ADT transcriptionally induces NE genes in PCa cells. CREB1 and REST are known to positively and negatively...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Journal Experts
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10602109/ https://www.ncbi.nlm.nih.gov/pubmed/37886478 http://dx.doi.org/10.21203/rs.3.rs-3270539/v1 |
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author | Li, Wenliang Zheng, Dayong Zhang, Yan Yang, Sukjin Su, Ning Bakhoum, Michael Zhang, Guoliang Naderinezhad, Samira Mao, Zhengmei Wang, Zheng Zhou, Ting |
author_facet | Li, Wenliang Zheng, Dayong Zhang, Yan Yang, Sukjin Su, Ning Bakhoum, Michael Zhang, Guoliang Naderinezhad, Samira Mao, Zhengmei Wang, Zheng Zhou, Ting |
author_sort | Li, Wenliang |
collection | PubMed |
description | Although effective initially, prolonged androgen deprivation therapy (ADT) promotes neuroendocrine differentiation (NED) and prostate cancer (PCa) progression. It is incompletely understood how ADT transcriptionally induces NE genes in PCa cells. CREB1 and REST are known to positively and negatively regulate neuronal gene expression in the brain, respectively. No direct link between these two master neuronal regulators has been elucidated in the NED of PCa. We show that REST mRNA is downregulated in NEPC cell and mouse models, as well as in patient samples. Phenotypically, REST overexpression increases ADT sensitivity, represses NE genes, inhibits colony formation in culture, and xenograft tumor growth of PCa cells. As expected, ADT downregulates REST in PCa cells in culture and in mouse xenografts. Interestingly, CREB1 signaling represses REST expression. In studying the largely unclear mechanism underlying transcriptional repression of REST by ADT, we found that REST is a direct target of EZH2 epigenetic repression. Finally, genetic rescue experiments demonstrated that ADT induces NED through EZH2’s repression of REST, which is enhanced by ADT-activated CREB signaling. In summary, our study has revealed a key pathway underlying NE gene upregulation by ADT, as well as established novel relationships between CREB1 and REST, and between EZH2 and REST, which may also have implications in other cancer types and in neurobiology. |
format | Online Article Text |
id | pubmed-10602109 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Journal Experts |
record_format | MEDLINE/PubMed |
spelling | pubmed-106021092023-10-27 Androgen deprivation induces neuroendocrine phenotypes in prostate cancer cells through CREB1/EZH2-mediated downregulation of REST Li, Wenliang Zheng, Dayong Zhang, Yan Yang, Sukjin Su, Ning Bakhoum, Michael Zhang, Guoliang Naderinezhad, Samira Mao, Zhengmei Wang, Zheng Zhou, Ting Res Sq Article Although effective initially, prolonged androgen deprivation therapy (ADT) promotes neuroendocrine differentiation (NED) and prostate cancer (PCa) progression. It is incompletely understood how ADT transcriptionally induces NE genes in PCa cells. CREB1 and REST are known to positively and negatively regulate neuronal gene expression in the brain, respectively. No direct link between these two master neuronal regulators has been elucidated in the NED of PCa. We show that REST mRNA is downregulated in NEPC cell and mouse models, as well as in patient samples. Phenotypically, REST overexpression increases ADT sensitivity, represses NE genes, inhibits colony formation in culture, and xenograft tumor growth of PCa cells. As expected, ADT downregulates REST in PCa cells in culture and in mouse xenografts. Interestingly, CREB1 signaling represses REST expression. In studying the largely unclear mechanism underlying transcriptional repression of REST by ADT, we found that REST is a direct target of EZH2 epigenetic repression. Finally, genetic rescue experiments demonstrated that ADT induces NED through EZH2’s repression of REST, which is enhanced by ADT-activated CREB signaling. In summary, our study has revealed a key pathway underlying NE gene upregulation by ADT, as well as established novel relationships between CREB1 and REST, and between EZH2 and REST, which may also have implications in other cancer types and in neurobiology. American Journal Experts 2023-10-04 /pmc/articles/PMC10602109/ /pubmed/37886478 http://dx.doi.org/10.21203/rs.3.rs-3270539/v1 Text en https://creativecommons.org/licenses/by/4.0/License:This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License (https://creativecommons.org/licenses/by/4.0/) https://creativecommons.org/licenses/by/4.0/This work is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/) , which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. |
spellingShingle | Article Li, Wenliang Zheng, Dayong Zhang, Yan Yang, Sukjin Su, Ning Bakhoum, Michael Zhang, Guoliang Naderinezhad, Samira Mao, Zhengmei Wang, Zheng Zhou, Ting Androgen deprivation induces neuroendocrine phenotypes in prostate cancer cells through CREB1/EZH2-mediated downregulation of REST |
title | Androgen deprivation induces neuroendocrine phenotypes in prostate cancer cells through CREB1/EZH2-mediated downregulation of REST |
title_full | Androgen deprivation induces neuroendocrine phenotypes in prostate cancer cells through CREB1/EZH2-mediated downregulation of REST |
title_fullStr | Androgen deprivation induces neuroendocrine phenotypes in prostate cancer cells through CREB1/EZH2-mediated downregulation of REST |
title_full_unstemmed | Androgen deprivation induces neuroendocrine phenotypes in prostate cancer cells through CREB1/EZH2-mediated downregulation of REST |
title_short | Androgen deprivation induces neuroendocrine phenotypes in prostate cancer cells through CREB1/EZH2-mediated downregulation of REST |
title_sort | androgen deprivation induces neuroendocrine phenotypes in prostate cancer cells through creb1/ezh2-mediated downregulation of rest |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10602109/ https://www.ncbi.nlm.nih.gov/pubmed/37886478 http://dx.doi.org/10.21203/rs.3.rs-3270539/v1 |
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