TLE3 loss confers AR inhibitor resistance by facilitating GR-mediated human prostate cancer cell growth
- Netherlands Cancer Institute, Netherlands
- Semmelweis University, Hungary
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.
Data availability
Data for Figure 1 (CRISPR resistance screen) is provided (source data file for Figure 1).Data for Figure 2 (RNA-seq) have been deposited in GEO under accession code GSE130246.Data (ChIP-seq) for Figure 3 and 4 is publicly available (GSE94682).Data for Figure 5C is the TCGA dataset (publicly available).
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RNA-seq control (sgNT) and TLE3KO (sgTLE3) cells treated with 10 uM enzalutamide or vehicleNCBI Gene Expression Omnibus, GSE130246.
Article and author information
Author details
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
- Myles Brown, Dana-Farber Cancer Institute, United States
Version history
- Received: April 4, 2019
- Accepted: December 19, 2019
- Accepted Manuscript published: December 19, 2019 (version 1)
- 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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TLE3 loss confers AR inhibitor resistance by facilitating GR-mediated human prostate cancer cell growth
eLife 8:e47430.
https://doi.org/10.7554/eLife.47430
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