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

eLife

Roderick Beijersbergen¹  Suzan Stelloo¹  Michiel S van der Heijden²  Tonći Šuštić³  Wilbert Zwart⁴  Lodewyk FA Wessels⁵  Daniel Vis⁶  Andries M Bergman⁶  Sander AL Palit⁶  Stefan Prekovic⁶  Balázs Győrffy⁶  Liesanne Wolters⁶  Elise Bekers⁷  Cor Lieftink⁷  Ingrid Hofland⁸ 

[1] Division of Molecular Carcinogenesis, Oncode Institute, Netherlands Cancer Institute, Amsterdam, Netherlands;TTK Cancer Biomarker Research Group, Institute of Enzymology, Budapest, Hungary;Core Facility Molecular Pathology & Biobanking, Netherlands Cancer Institute, Amsterdam, Netherlands;Department of Bioinformatics, Semmelweis University, Budapest, Hungary;Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands;Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, Netherlands;Division of Oncogenomics, Oncode Institute, Netherlands Cancer Institute, Amsterdam, Netherlands;Division of Pathology, Netherlands Cancer Institute, Amsterdam, Netherlands;

关键词: prostate cancer;    therapy resistance;    androgen receptor;    TLE3;    glucocorticoid receptor;    Enzalutamide;   

DOI  :  10.7554/eLife.47430

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown