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CREB5 reprograms FOXA1 nuclear interactions to promote resistance to androgen receptor-targeting therapies
Metastatic castration-resistant prostate cancers (mCRPCs) are treated with therapies that antagonize the androgen receptor (AR). Nearly all patients develop resistance to AR-targeted therapies (ARTs). Our previous work identified CREB5 as an upregulated target gene in human mCRPC that promoted resis...
Autores principales: | , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9135408/ https://www.ncbi.nlm.nih.gov/pubmed/35550030 http://dx.doi.org/10.7554/eLife.73223 |
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author | Hwang, Justin H Arafeh, Rand Seo, Ji-Heui Baca, Sylvan C Ludwig, Megan Arnoff, Taylor E Sawyer, Lydia Richter, Camden Tape, Sydney Bergom, Hannah E McSweeney, Sean Rennhack, Jonathan P Klingenberg, Sarah A Cheung, Alexander TM Kwon, Jason So, Jonathan Kregel, Steven Van Allen, Eliezer M Drake, Justin M Freedman, Matthew L Hahn, William C |
author_facet | Hwang, Justin H Arafeh, Rand Seo, Ji-Heui Baca, Sylvan C Ludwig, Megan Arnoff, Taylor E Sawyer, Lydia Richter, Camden Tape, Sydney Bergom, Hannah E McSweeney, Sean Rennhack, Jonathan P Klingenberg, Sarah A Cheung, Alexander TM Kwon, Jason So, Jonathan Kregel, Steven Van Allen, Eliezer M Drake, Justin M Freedman, Matthew L Hahn, William C |
author_sort | Hwang, Justin H |
collection | PubMed |
description | Metastatic castration-resistant prostate cancers (mCRPCs) are treated with therapies that antagonize the androgen receptor (AR). Nearly all patients develop resistance to AR-targeted therapies (ARTs). Our previous work identified CREB5 as an upregulated target gene in human mCRPC that promoted resistance to all clinically approved ART. The mechanisms by which CREB5 promotes progression of mCRPC or other cancers remains elusive. Integrating ChIP-seq and rapid immunoprecipitation and mass spectroscopy of endogenous proteins, we report that cells overexpressing CREB5 demonstrate extensive reprogramming of nuclear protein–protein interactions in response to the ART agent enzalutamide. Specifically, CREB5 physically interacts with AR, the pioneering actor FOXA1, and other known co-factors of AR and FOXA1 at transcription regulatory elements recently found to be active in mCRPC patients. We identified a subset of CREB5/FOXA1 co-interacting nuclear factors that have critical functions for AR transcription (GRHL2, HOXB13) while others (TBX3, NFIC) regulated cell viability and ART resistance and were amplified or overexpressed in mCRPC. Upon examining the nuclear protein interactions and the impact of CREB5 expression on the mCRPC patient transcriptome, we found that CREB5 was associated with Wnt signaling and epithelial to mesenchymal transitions, implicating these pathways in CREB5/FOXA1-mediated ART resistance. Overall, these observations define the molecular interactions among CREB5, FOXA1, and pathways that promote ART resistance. |
format | Online Article Text |
id | pubmed-9135408 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-91354082022-05-27 CREB5 reprograms FOXA1 nuclear interactions to promote resistance to androgen receptor-targeting therapies Hwang, Justin H Arafeh, Rand Seo, Ji-Heui Baca, Sylvan C Ludwig, Megan Arnoff, Taylor E Sawyer, Lydia Richter, Camden Tape, Sydney Bergom, Hannah E McSweeney, Sean Rennhack, Jonathan P Klingenberg, Sarah A Cheung, Alexander TM Kwon, Jason So, Jonathan Kregel, Steven Van Allen, Eliezer M Drake, Justin M Freedman, Matthew L Hahn, William C eLife Cancer Biology Metastatic castration-resistant prostate cancers (mCRPCs) are treated with therapies that antagonize the androgen receptor (AR). Nearly all patients develop resistance to AR-targeted therapies (ARTs). Our previous work identified CREB5 as an upregulated target gene in human mCRPC that promoted resistance to all clinically approved ART. The mechanisms by which CREB5 promotes progression of mCRPC or other cancers remains elusive. Integrating ChIP-seq and rapid immunoprecipitation and mass spectroscopy of endogenous proteins, we report that cells overexpressing CREB5 demonstrate extensive reprogramming of nuclear protein–protein interactions in response to the ART agent enzalutamide. Specifically, CREB5 physically interacts with AR, the pioneering actor FOXA1, and other known co-factors of AR and FOXA1 at transcription regulatory elements recently found to be active in mCRPC patients. We identified a subset of CREB5/FOXA1 co-interacting nuclear factors that have critical functions for AR transcription (GRHL2, HOXB13) while others (TBX3, NFIC) regulated cell viability and ART resistance and were amplified or overexpressed in mCRPC. Upon examining the nuclear protein interactions and the impact of CREB5 expression on the mCRPC patient transcriptome, we found that CREB5 was associated with Wnt signaling and epithelial to mesenchymal transitions, implicating these pathways in CREB5/FOXA1-mediated ART resistance. Overall, these observations define the molecular interactions among CREB5, FOXA1, and pathways that promote ART resistance. eLife Sciences Publications, Ltd 2022-05-12 /pmc/articles/PMC9135408/ /pubmed/35550030 http://dx.doi.org/10.7554/eLife.73223 Text en © 2022, Hwang, Arafeh, Seo et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Cancer Biology Hwang, Justin H Arafeh, Rand Seo, Ji-Heui Baca, Sylvan C Ludwig, Megan Arnoff, Taylor E Sawyer, Lydia Richter, Camden Tape, Sydney Bergom, Hannah E McSweeney, Sean Rennhack, Jonathan P Klingenberg, Sarah A Cheung, Alexander TM Kwon, Jason So, Jonathan Kregel, Steven Van Allen, Eliezer M Drake, Justin M Freedman, Matthew L Hahn, William C CREB5 reprograms FOXA1 nuclear interactions to promote resistance to androgen receptor-targeting therapies |
title | CREB5 reprograms FOXA1 nuclear interactions to promote resistance to androgen receptor-targeting therapies |
title_full | CREB5 reprograms FOXA1 nuclear interactions to promote resistance to androgen receptor-targeting therapies |
title_fullStr | CREB5 reprograms FOXA1 nuclear interactions to promote resistance to androgen receptor-targeting therapies |
title_full_unstemmed | CREB5 reprograms FOXA1 nuclear interactions to promote resistance to androgen receptor-targeting therapies |
title_short | CREB5 reprograms FOXA1 nuclear interactions to promote resistance to androgen receptor-targeting therapies |
title_sort | creb5 reprograms foxa1 nuclear interactions to promote resistance to androgen receptor-targeting therapies |
topic | Cancer Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9135408/ https://www.ncbi.nlm.nih.gov/pubmed/35550030 http://dx.doi.org/10.7554/eLife.73223 |
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