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

Sander A.L. Palit; 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

doi:10.7554/eLife.47430

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)

Chemical Biology

Research output: Contribution to journal › Article › Academic › peer-review

26 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 TLE3^KO 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 language	English
Article number	e47430
Number of pages	17
Journal	eLife
Volume	8
DOIs	https://doi.org/10.7554/eLife.47430
Publication status	Published - 19 Dec 2019

Funding

This work was funded by a KWF-Alpe d’HuZes grant (NKI 2014-7080). S. Stelloo is funded by the Movember Foundation, and W. Zwart is supported by a KWF-Alpe d’HuZes Bas Mulder Award and Netherlands Scientific Organization NWO VIDI grant. We would like to acknowledge Yanyun Zhu for technical support and helpful discussions. The authors thank the NKI Genomics Core Facility for bioinformatics support. We would like to acknowledge the NKI-AVL Core Facility Molecular Pathology & Biobanking (CFMPB) for supplying NKI-AVL Biobank material and lab support.

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.7554/eLife.47430

Cite this

Palit, S. A. L., Vis, D., Stelloo, S., Lieftink, C., Prekovic, S., Bekers, E., Hofland, I., Šuštić, T., Wolters, L., Beijersbergen, R., Bergman, A. M., Győrffy, B., Wessels, L. F. A., Zwart, W., & van der Heijden, M. S. (2019). TLE3 loss confers AR inhibitor resistance by facilitating GR-mediated human prostate cancer cell growth. eLife, 8, Article e47430. https://doi.org/10.7554/eLife.47430

@article{9e1e0d8b09684afbad2965c3fbed657f,

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

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.",

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",

author = "Palit, {Sander A.L.} and Daniel Vis and Suzan Stelloo and Cor Lieftink and Stefan Prekovic and Elise Bekers and Ingrid Hofland and Ton{\'c}i {\v S}u{\v s}ti{\'c} and Liesanne Wolters and Roderick Beijersbergen and Bergman, {Andries M.} and Bal{\'a}zs Gy{\H o}rffy and Wessels, {Lodewyk F.A.} and Wilbert Zwart and {van der Heijden}, {Michiel S.}",

year = "2019",

month = dec,

day = "19",

doi = "10.7554/eLife.47430",

language = "English",

volume = "8",

journal = "eLife",

issn = "2050-084X",

publisher = "eLife Sciences Publications Ltd",

}

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 - 2019/12/19

Y1 - 2019/12/19

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.

KW - AR

KW - CRISPR-Cas9 screen

KW - Drug resistance

KW - Enzalutamide

KW - GR

KW - Prostate cancer

KW - TLE3

KW - Androgen Receptor Antagonists/pharmacology

KW - Humans

KW - Male

KW - Gene Expression Regulation, Neoplastic/drug effects

KW - Prostate/metabolism

KW - Hepatocyte Nuclear Factor 3-alpha/genetics

KW - Phenylthiohydantoin/analogs & derivatives

KW - CRISPR-Cas Systems/genetics

KW - Receptors, Androgen/genetics

KW - Drug Resistance, Neoplasm/genetics

KW - HEK293 Cells

KW - Cell Line, Tumor

KW - Transcriptional Activation/drug effects

KW - Prostatic Neoplasms/drug therapy

KW - Receptors, Glucocorticoid/genetics

KW - Cell Proliferation/drug effects

KW - Co-Repressor Proteins/genetics

UR - http://www.scopus.com/inward/record.url?scp=85077548136&partnerID=8YFLogxK

U2 - 10.7554/eLife.47430

DO - 10.7554/eLife.47430

M3 - Article

C2 - 31855178

AN - SCOPUS:85077548136

SN - 2050-084X

VL - 8

JO - eLife

JF - eLife

M1 - e47430

ER -

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

Abstract

Funding

Keywords

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this