TY - JOUR
T1 - TLE3 loss confers AR inhibitor resistance by facilitating GR-mediated human prostate cancer cell growth
AU - Palit, Sander A. L.
AU - Vis, Daniel
AU - Stelloo, Suzan
AU - Lieftink, Cor
AU - Prekovic, Stefan
AU - Bekers, Elise
AU - Hofland, Ingrid
AU - Šuštić, Tonći
AU - Wolters, Liesanne
AU - Beijersbergen, Roderick
AU - Bergman, Andries M.
AU - Győrffy, Balázs
AU - Wessels, Lodewyk F. A.
AU - Zwart, Wilbert
AU - van der Heijden, Michiel S.
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85077548136&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/31855178
U2 - https://doi.org/10.7554/eLife.47430
DO - https://doi.org/10.7554/eLife.47430
M3 - Article
C2 - 31855178
SN - 2050-084X
VL - 8
JO - eLife
JF - eLife
M1 - e47430
ER -