A novel CRISPR-engineered prostate cancer cell line defines the AR-V transcriptome and identifies PARP inhibitor sensitivities.
Algorithms
CRISPR-Cas Systems
Cell Line, Tumor
Cell Proliferation
DNA Damage
DNA Repair
Drug Screening Assays, Antitumor
Genetic Techniques
Humans
Lentivirus
Male
Poly(ADP-ribose) Polymerase Inhibitors
/ pharmacology
Prostatic Neoplasms
/ genetics
Receptors, Androgen
/ biosynthesis
Sequence Analysis, RNA
Transcriptome
Journal
Nucleic acids research
ISSN: 1362-4962
Titre abrégé: Nucleic Acids Res
Pays: England
ID NLM: 0411011
Informations de publication
Date de publication:
20 06 2019
20 06 2019
Historique:
accepted:
10
04
2019
revised:
13
03
2019
received:
30
11
2018
pubmed:
23
4
2019
medline:
4
12
2019
entrez:
23
4
2019
Statut:
ppublish
Résumé
Resistance to androgen receptor (AR)-targeted therapies in prostate cancer (PC) is a major clinical problem. A key mechanism of treatment resistance in advanced PC is the generation of alternatively spliced forms of the AR termed AR variants (AR-Vs) that are refractory to targeted agents and drive tumour progression. Our understanding of how AR-Vs function is limited due to difficulties in distinguishing their discriminate activities from full-length AR (FL-AR). Here we report the development of a novel CRISPR-derived cell line which is a derivative of CWR22Rv1 cells, called CWR22Rv1-AR-EK, that has lost expression of FL-AR, but retains all endogenous AR-Vs. From this, we show that AR-Vs act unhindered by loss of FL-AR to drive cell growth and expression of androgenic genes. Global transcriptomics demonstrate that AR-Vs drive expression of a cohort of DNA damage response genes and depletion of AR-Vs sensitises cells to ionising radiation. Moreover, we demonstrate that AR-Vs interact with PARP1 and PARP2 and are dependent upon their catalytic function for transcriptional activation. Importantly, PARP blockade compromises expression of AR-V-target genes and reduces growth of CRPC cell lines suggesting a synthetic lethality relationship between AR-Vs and PARP, advocating the use of PARP inhibitors in AR-V positive PC.
Identifiants
pubmed: 31006810
pii: 5475935
doi: 10.1093/nar/gkz286
pmc: PMC6582326
doi:
Substances chimiques
AR protein, human
0
Poly(ADP-ribose) Polymerase Inhibitors
0
Receptors, Androgen
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
5634-5647Subventions
Organisme : NCI NIH HHS
ID : R01 CA174777
Pays : United States
Organisme : Medical Research Council
ID : MR/P009972/1
Pays : United Kingdom
Informations de copyright
© The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.
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