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

Sander A.L. Palit (Corresponding author), Daniel Vis, Suzan Stelloo, Cor Lieftink, Stefan Prekovic, Elise Bekers, Ingrid Hofland, Tonći Šuštić, Liesanne Wolters, Roderick Beijersbergen, Andries M. Bergman, Balázs Győrffy, Lodewyk F.A. Wessels, Wilbert Zwart, Michiel S. van der Heijden (Corresponding author)

Research output: Contribution to journalArticleAcademicpeer-review

20 Citations (Scopus)

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.

Original languageEnglish
Article numbere47430
Number of pages17
JournaleLife
Volume8
DOIs
Publication statusPublished - 19 Dec 2019

Keywords

  • AR
  • CRISPR-Cas9 screen
  • Drug resistance
  • Enzalutamide
  • GR
  • Prostate cancer
  • TLE3
  • Androgen Receptor Antagonists/pharmacology
  • Humans
  • Male
  • Gene Expression Regulation, Neoplastic/drug effects
  • Prostate/metabolism
  • Hepatocyte Nuclear Factor 3-alpha/genetics
  • Phenylthiohydantoin/analogs & derivatives
  • CRISPR-Cas Systems/genetics
  • Receptors, Androgen/genetics
  • Drug Resistance, Neoplasm/genetics
  • HEK293 Cells
  • Cell Line, Tumor
  • Transcriptional Activation/drug effects
  • Prostatic Neoplasms/drug therapy
  • Receptors, Glucocorticoid/genetics
  • Cell Proliferation/drug effects
  • Co-Repressor Proteins/genetics

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