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

Eugine Lee, John Wongvipat, Danielle Choi, Ping Wang, Young Sun Lee, Deyou Zheng, Philip A. Watson, Anuradha Gopalan, Charles L. Sawyers

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournaleLife
Volume8
DOIs
StatePublished - Jan 15 2019

Fingerprint

Androgen Antagonists
Androgen Receptors
Prostatic Neoplasms
Genes
Small Interfering RNA
Amplification
Up-Regulation
Cells

Keywords

  • AR coactivator
  • AR signaling output
  • cancer biology
  • enzalutamide
  • GREB1
  • human
  • intra-tumoral heterogeneity

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

GREB1 amplifies androgen receptor output in human prostate cancer and contributes to antiandrogen resistance. / Lee, Eugine; Wongvipat, John; Choi, Danielle; Wang, Ping; Lee, Young Sun; Zheng, Deyou; Watson, Philip A.; Gopalan, Anuradha; Sawyers, Charles L.

In: eLife, Vol. 8, 15.01.2019.

Research output: Contribution to journalArticle

Lee, E, Wongvipat, J, Choi, D, Wang, P, Lee, YS, Zheng, D, Watson, PA, Gopalan, A & Sawyers, CL 2019, 'GREB1 amplifies androgen receptor output in human prostate cancer and contributes to antiandrogen resistance', eLife, vol. 8. https://doi.org/10.7554/eLife.41913
Lee, Eugine ; Wongvipat, John ; Choi, Danielle ; Wang, Ping ; Lee, Young Sun ; Zheng, Deyou ; Watson, Philip A. ; Gopalan, Anuradha ; Sawyers, Charles L. / GREB1 amplifies androgen receptor output in human prostate cancer and contributes to antiandrogen resistance. In: eLife. 2019 ; Vol. 8.
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AU - Zheng, Deyou

AU - Watson, Philip A.

AU - Gopalan, Anuradha

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