CREB5 reprograms FOXA1 nuclear interactions to promote resistance to androgen receptor targeting therapies

  1. Justin H Hwang  Is a corresponding author
  2. Rand Arafeh
  3. Ji-Heui Seo
  4. Sylvan C Baca
  5. Megan Ludwig
  6. Taylor E Arnoff
  7. Lydia Sawyer
  8. Camden Richter
  9. Sydney Tape
  10. Hannah E Bergom
  11. Sean McSweeney
  12. Jonathan P Rennhack
  13. Sarah A Klingenberg
  14. Alexander TM Cheung
  15. Jason Kwon
  16. Jonathan So
  17. Steven Kregel
  18. Eliezer M Van Allen
  19. Justin M Drake
  20. Matthew L Freedman
  21. William C Hahn  Is a corresponding author
  1. University of Minnesota, United States
  2. Dana-Farber Cancer Institue, United States
  3. Brown University, United States
  4. New York University, United States
  5. Dana-Farber Cancer Institute, United States
  6. Loyola University Chicago, United States

Abstract

Metastatic castration resistant prostate cancers (mCRPC) are treated with therapies that antagonize the androgen receptor (AR). Nearly all patients develop resistance to AR-targeted therapies (ART). 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 (RIME), 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 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.

Data availability

RIME data has been shared through supplementary tables.

The following previously published data sets were used

Article and author information

Author details

  1. Justin H Hwang

    Masonic Cancer Center, University of Minnesota, Minneapolis, United States
    For correspondence
    jhwang@umn.edu
    Competing interests
    Justin H Hwang, is a consultant for Astrin Biosciences, Principal Investigator for Caris Life Sciences Genitourinary disease working group..
  2. Rand Arafeh

    Department of Medical Oncology, Dana-Farber Cancer Institue, Boston, United States
    Competing interests
    No competing interests declared.
  3. Ji-Heui Seo

    Department of Medical Oncology, Dana-Farber Cancer Institue, Boston, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7280-3334
  4. Sylvan C Baca

    Department of Medical Oncology, Dana-Farber Cancer Institue, Boston, United States
    Competing interests
    No competing interests declared.
  5. Megan Ludwig

    Department of Pharmacology, University of Minnesota, Minneapolis, United States
    Competing interests
    No competing interests declared.
  6. Taylor E Arnoff

    Brown University, Providence, United States
    Competing interests
    No competing interests declared.
  7. Lydia Sawyer

    Department of Medical Oncology, Dana-Farber Cancer Institue, Boston, United States
    Competing interests
    No competing interests declared.
  8. Camden Richter

    Department of Medical Oncology, Dana-Farber Cancer Institue, Boston, United States
    Competing interests
    No competing interests declared.
  9. Sydney Tape

    Department of Medicine, University of Minnesota, Minneapolis, United States
    Competing interests
    No competing interests declared.
  10. Hannah E Bergom

    Department of Medicine, University of Minnesota, Minneapolis, United States
    Competing interests
    No competing interests declared.
  11. Sean McSweeney

    Department of Medicine, University of Minnesota, Minneapolis, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7682-2073
  12. Jonathan P Rennhack

    Department of Medical Oncology, Dana-Farber Cancer Institue, Boston, United States
    Competing interests
    No competing interests declared.
  13. Sarah A Klingenberg

    Department of Medicine, University of Minnesota, Minneapolis, United States
    Competing interests
    No competing interests declared.
  14. Alexander TM Cheung

    Grossman School of Medicine, New York University, New York, United States
    Competing interests
    No competing interests declared.
  15. Jason Kwon

    Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  16. Jonathan So

    1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  17. Steven Kregel

    Department of Cancer Biology, Loyola University Chicago, Maywood, United States
    Competing interests
    No competing interests declared.
  18. Eliezer M Van Allen

    Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    Eliezer M Van Allen, serves as Advisory/Consulting for Tango Therapeutics, Genome Medical, Invitae, Enara Bio, Janssen, Manifold Bio, Monte Rosa, received research support from Novartis, BMS, has equity with Tango Therapeutics, Genome Medical, Syapse, Enara Bio, Manifold Bio, Microsoft, Monte Rosa, receives travel reimbursement from Roche/Genentech, and holds patents including Institutional patents filed on chromatin mutations and immunotherapy response, and methods for clinical interpretation..
  19. Justin M Drake

    Department of Pharmacology and Urology, University of Minnesota, Minneapolis, United States
    Competing interests
    No competing interests declared.
  20. Matthew L Freedman

    Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  21. William C Hahn

    Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States
    For correspondence
    william_hahn@dfci.harvard.edu
    Competing interests
    William C Hahn, Reviewing editor, eLife.Is a consultant for ThermoFisher, Solasta Ventures, MPM Capital, KSQ Therapeutics, Tyra Biosciences, Frontier Medicine, Jubilant Therapeutics, RAPPTA Therapeutics, Function Oncology and Calyx..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2840-9791

Funding

University of Minnesota (Start up funds)

  • Justin H Hwang

National Cancer Institute (U01 CA176058)

  • William C Hahn

National Cancer Institute (U01 CA233100)

  • Eliezer M Van Allen

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Charles L Sawyers, Memorial Sloan Kettering Cancer Center, United States

Publication history

  1. Received: August 20, 2021
  2. Accepted: May 11, 2022
  3. Accepted Manuscript published: May 12, 2022 (version 1)

Copyright

© 2022, Hwang et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Justin H Hwang
  2. Rand Arafeh
  3. Ji-Heui Seo
  4. Sylvan C Baca
  5. Megan Ludwig
  6. Taylor E Arnoff
  7. Lydia Sawyer
  8. Camden Richter
  9. Sydney Tape
  10. Hannah E Bergom
  11. Sean McSweeney
  12. Jonathan P Rennhack
  13. Sarah A Klingenberg
  14. Alexander TM Cheung
  15. Jason Kwon
  16. Jonathan So
  17. Steven Kregel
  18. Eliezer M Van Allen
  19. Justin M Drake
  20. Matthew L Freedman
  21. William C Hahn
(2022)
CREB5 reprograms FOXA1 nuclear interactions to promote resistance to androgen receptor targeting therapies
eLife 11:e73223.
https://doi.org/10.7554/eLife.73223

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