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TLE3 loss confers AR inhibitor resistance by facilitating GR-mediated human prostate cancer cell growth

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Cite this article as: eLife 2019;8:e47430 doi: 10.7554/eLife.47430

Abstract

Androgen receptor (AR) inhibitors represent the mainstay of prostate cancer treatment. In a genome-wide CRISPR-Cas9 screen using LNCaP prostate cancer cells, loss of co-repressor TLE3 conferred resistance to AR antagonists apalutamide and enzalutamide. Genes differentially expressed upon TLE3 loss share AR as the top transcriptional regulator, and TLE3 loss rescued the expression of a subset of androgen-responsive genes upon enzalutamide treatment. GR expression was strongly upregulated upon AR inhibition in a TLE3-negative background. This was consistent with binding of TLE3 and AR at the GR locus. Furthermore, GR binding was observed proximal to TLE3/AR-shared genes. GR inhibition resensitized TLE3KO cells to enzalutamide. Analyses of patient samples revealed an association between TLE3 and GR levels that reflected our findings in LNCaP cells, of which the clinical relevance is yet to be determined. Together, our findings reveal a mechanistic link between TLE3 and GR-mediated resistance to AR inhibitors in human prostate cancer.

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Author details

  1. Sander AL Palit

    Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, Netherlands
    For correspondence
    s.palit@nki.nl
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2487-4311
  2. Daniel Vis

    Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, Netherlands
    Competing interests
    No competing interests declared.
  3. Suzan Stelloo

    Division of Oncogenomics, Oncode Institute, Netherlands Cancer Institute, Amsterdam, Netherlands
    Competing interests
    No competing interests declared.
  4. Cor Lieftink

    Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, Netherlands
    Competing interests
    No competing interests declared.
  5. Stefan Prekovic

    Division of Oncogenomics, Oncode Institute, Netherlands Cancer Institute, Amsterdam, Netherlands
    Competing interests
    No competing interests declared.
  6. Elise Bekers

    Division of Pathology, Netherlands Cancer Institute, Amsterdam, Netherlands
    Competing interests
    No competing interests declared.
  7. Ingrid Hofland

    Core Facility Molecular Pathology and Biobanking, Netherlands Cancer Institute, Amsterdam, Netherlands
    Competing interests
    No competing interests declared.
  8. Tonći Šuštić

    Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, Netherlands
    Competing interests
    No competing interests declared.
  9. Liesanne Wolters

    Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, Netherlands
    Competing interests
    No competing interests declared.
  10. Roderick Beijersbergen

    Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, Netherlands
    Competing interests
    No competing interests declared.
  11. Andries M Bergman

    Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands
    Competing interests
    No competing interests declared.
  12. Balázs Győrffy

    TTK Cancer Biomarker Research Group, Institute of Enzymology, Semmelweis University, Budapest, Hungary
    Competing interests
    No competing interests declared.
  13. Lodewyk FA Wessels

    Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, Netherlands
    Competing interests
    No competing interests declared.
  14. Wilbert Zwart

    Division of Oncogenomics, Oncode Institute, Netherlands Cancer Institute, Amsterdam, Netherlands
    Competing interests
    Wilbert Zwart, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9823-7289
  15. Michiel S van der Heijden

    Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, Netherlands
    For correspondence
    ms.vd.heijden@nki.nl
    Competing interests
    No competing interests declared.

Funding

KWF Kankerbestrijding (NKI2014-7080)

  • Michiel S van der Heijden

KWF Kankerbestrijding (NKI2014-7080)

  • Andries M Bergman

KWF Kankerbestrijding (NKI2014-7080)

  • Wilbert Zwart

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

Reviewing Editor

  1. Myles Brown, Dana-Farber Cancer Institute, United States

Publication history

  1. Received: April 4, 2019
  2. Accepted: December 19, 2019
  3. Accepted Manuscript published: December 19, 2019 (version 1)
  4. Version of Record published: January 17, 2020 (version 2)

Copyright

© 2019, Palit 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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