GREB1 amplifies androgen receptor output in human prostate cancer and contributes to antiandrogen resistance

  1. Eugine Lee
  2. John Wongvipat
  3. Danielle Choi
  4. Ping Wang
  5. Young Sun Lee
  6. Deyou Zheng
  7. Philip A Watson
  8. Anuradha Gopalan
  9. Charles L Sawyers  Is a corresponding author
  1. Memorial Sloan Kettering Cancer Center, United States
  2. Albert Einstein College of Medicine, United States

Abstract

Genomic amplification of the androgen receptor (AR) is an established mechanism of antiandrogen resistance in prostate cancer. Here we show that the magnitude of AR signaling output, independent of AR genomic alteration or expression level, also contributes to antiandrogen resistance, through upregulation of the coactivator GREB1. We demonstrate 100-fold heterogeneity in AR output within human prostate cancer cell lines and show that cells with high AR output have reduced sensitivity to enzalutamide. Through transcriptomic and shRNA knockdown studies, together with analysis of clinical datasets, we identify GREB1 as a gene responsible for high AR output. We show that GREB1 is an AR target gene that amplifies AR output by enhancing AR DNA binding and promoting EP300 recruitment. GREB1 knockdown in high AR output cells restores enzalutamide sensitivity in vivo. Thus, GREB1 is a candidate driver of enzalutamide resistance through a novel feed forward mechanism.

Data availability

RNA-seq data has been deposited in GEO under accession code GSE120720. ChIP-seq data has been deposited in GEO under accession code GSE120680

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Eugine Lee

    Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    No competing interests declared.
  2. John Wongvipat

    Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    John Wongvipat, co-inventor of enzalutamide.
  3. Danielle Choi

    Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    No competing interests declared.
  4. Ping Wang

    Department of Genetics, Albert Einstein College of Medicine, New York, United States
    Competing interests
    No competing interests declared.
  5. Young Sun Lee

    Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    No competing interests declared.
  6. Deyou Zheng

    Department of Genetics, Albert Einstein College of Medicine, New York, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4354-5337
  7. Philip A Watson

    Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    No competing interests declared.
  8. Anuradha Gopalan

    Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    No competing interests declared.
  9. Charles L Sawyers

    Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States
    For correspondence
    sawyersc@mskcc.org
    Competing interests
    Charles L Sawyers, Senior editor, eLife; Board of Directors of Novartis; co-founder of ORIC Pharm; co-inventor of enzalutamide and apalutamide; Science advisor to Agios, Beigene, Blueprint, Column Group, Foghorn, Housey Pharma, Nextech, KSQ, Petra and PMV; co-founder of Seragon, purchased by Genentech/Roche in 2014.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4955-6475

Funding

Howard Hughes Medical Institute

  • Charles L Sawyers

National Institutes of Health (CA008748)

  • Charles L Sawyers

National Institutes of Health (CA155169)

  • Charles L Sawyers

U.S. Department of Defense (W81XWH-15-1-0540)

  • Eugine Lee

Starr Cancer Consortium (I10-0062)

  • Charles L Sawyers

Iris & Junming Le Foundation

  • Eugine Lee

National Institutes of Health (CA193837)

  • Charles L Sawyers

National Institutes of Health (CA224079)

  • Charles L Sawyers

National Institutes of Health (CA092629)

  • Charles L Sawyers

National Institutes of Health (CA160001)

  • Charles L Sawyers

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

Ethics

Animal experimentation: All animal experiments were performed in compliance with the approved institutional animal care and use committee (IACUC) protocols (#06-07-012) of the Research Animal Resource Center of Memorial Sloan Kettering Cancer Center.

Copyright

© 2019, Lee 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.

Metrics

  • 2,637
    views
  • 407
    downloads
  • 19
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Eugine Lee
  2. John Wongvipat
  3. Danielle Choi
  4. Ping Wang
  5. Young Sun Lee
  6. Deyou Zheng
  7. Philip A Watson
  8. Anuradha Gopalan
  9. Charles L Sawyers
(2019)
GREB1 amplifies androgen receptor output in human prostate cancer and contributes to antiandrogen resistance
eLife 8:e41913.
https://doi.org/10.7554/eLife.41913

Share this article

https://doi.org/10.7554/eLife.41913

Further reading

    1. Cancer Biology
    Matthew Yorek, Xingshan Jiang ... Bing Li
    Research Article

    A high density of tumor-associated macrophages (TAMs) is associated with poorer prognosis and survival in breast cancer patients. Recent studies have shown that lipid accumulation in TAMs can promote tumor growth and metastasis in various models. However, the specific molecular mechanisms that drive lipid accumulation and tumor progression in TAMs remain largely unknown. Herein, we demonstrated that unsaturated fatty acids (FAs), unlike saturated ones, are more likely to form lipid droplets in murine macrophages. Specifically, unsaturated FAs, including linoleic acids (LA), activate the FABP4/CEBPα pathway, leading to triglyceride synthesis and lipid droplet formation. Furthermore, FABP4 enhances lipolysis and FA utilization by breast cancer cell lines, which promotes cancer cell migration in vitro and metastasis in vivo. Notably, a deficiency of FABP4 in murine macrophages significantly reduces LA-induced lipid metabolism. Therefore, our findings suggest FABP4 as a crucial lipid messenger that facilitates unsaturated FA-mediated lipid accumulation and lipolysis in TAMs, thus contributing to the metastasis of breast cancer.

    1. Cancer Biology
    2. Computational and Systems Biology
    Nayoung Kim, Sehhoon Park ... Myung-Ju Ahn
    Research Article

    This study investigates the variability among patients with non-small cell lung cancer (NSCLC) in their responses to immune checkpoint inhibitors (ICIs). Recognizing that patients with advanced-stage NSCLC rarely qualify for surgical interventions, it becomes crucial to identify biomarkers that influence responses to ICI therapy. We conducted an analysis of single-cell transcriptomes from 33 lung cancer biopsy samples, with a particular focus on 14 core samples taken before the initiation of palliative ICI treatment. Our objective was to link tumor and immune cell profiles with patient responses to ICI. We discovered that ICI non-responders exhibited a higher presence of CD4+ regulatory T cells, resident memory T cells, and TH17 cells. This contrasts with the diverse activated CD8+ T cells found in responders. Furthermore, tumor cells in non-responders frequently showed heightened transcriptional activity in the NF-kB and STAT3 pathways, suggesting a potential inherent resistance to ICI therapy. Through the integration of immune cell profiles and tumor molecular signatures, we achieved an discriminative power (area under the curve [AUC]) exceeding 95% in identifying patient responses to ICI treatment. These results underscore the crucial importance of the interplay between tumor and immune microenvironment, including within metastatic sites, in affecting the effectiveness of ICIs in NSCLC.