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Elife. 2019 Dec 19;8. pii: e47430. doi: 10.7554/eLife.47430.

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

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Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, Netherlands.
Division of Molecular Carcinogenesis, Oncode Institute, Netherlands Cancer Institute, Amsterdam, Netherlands.
Division of Oncogenomics, Oncode Institute, Netherlands Cancer Institute, Amsterdam, Netherlands.
Division of Pathology, Netherlands Cancer Institute, Amsterdam, Netherlands.
Core Facility Molecular Pathology & Biobanking, Netherlands Cancer Institute, Amsterdam, Netherlands.
Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands.
Department of Bioinformatics, Semmelweis University, Budapest, Hungary.
TTK Cancer Biomarker Research Group, Institute of Enzymology, Budapest, Hungary.
Department of Pediatrics, Semmelweis University, Budapest, Hungary.
Laboratory of Chemical Biology and Institute for Complex Molecular Systems, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, Netherlands.


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.


Enzalutamide; TLE3; androgen receptor; cancer biology; glucocorticoid receptor; human; prostate cancer; therapy resistance

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