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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2022
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.
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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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