GREB1 amplifies androgen receptor output in human prostate cancer and contributes to antiandrogen resistance
- Memorial Sloan Kettering Cancer Center, United States
- 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
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GREB1 amplifies androgen receptor output in prostate cancer and contributes to antiandrogen resistanceNCBI Gene Expression Omnibus, GSE120720.
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GREB1 amplifies androgen receptor output in prostate cancer and contributes to antiandrogen resistanceNCBI Gene Expression Omnibus, GSE120680.
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Integrative clinical genomics of advanced prostate cancerNCBI dbGap, phs000915.v1.p1.
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The Molecular Taxonomy of Primary Prostate CancercBioPortal for Cancer Genomics.
Article and author information
Author details
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.
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GREB1 amplifies androgen receptor output in human prostate cancer and contributes to antiandrogen resistance
eLife 8:e41913.
https://doi.org/10.7554/eLife.41913
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