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AR mRNA stability is increased with AR-antagonist resistance Via 3’ UTR variants

Title: AR mRNA stability is increased with AR-antagonist resistance Via 3’ UTR variants
Authors: Dart, D
Ashelford, K
Jiang, W
Item Type: Journal Article
Abstract: Advanced prostate cancer is often treated with AR-antagonists which target the androgen receptor (AR) on which the growth of the tumour depends. Prostate cancer often develops AR-antagonist resistance via a plethora of mechanisms, many of which are as yet unknown, but it is thought that AR upregulation or AR ligand binding site mutations, may be responsible. Here we describe the production of cell lines based on LNCaP and VCaP, with acquired resistance to the clinically relevant AR-antagonists, bicalutamide and enzalutamide.In these resistant cells, we observed, via RNA-seq, that new variants in the 3’UTR of the AR mRNA were detectable and that the levels were increased both with AR-antagonist treatment and with hormonal starvation. Around 20% of AR transcripts showed a 3kb deletion within the 6.7kb 3’UTR sequence. Actinomycin D and luciferase fusion studies indicated that this shorter mRNA variant was inherently more stable in anti-androgen resistant cell lines.Of additional interest was that the AR UTR variant could be detected in the sera of prostate cancer patients in a cohort of serum samples collected from patients of Gleason grades 6-10, with an increasing level correlated to increasing grade.We hypothesise that the shorter AR UTR variant is a survival adaptation to low hormone levels and/or AR-antagonist treatment in these cells, where a more stable mRNA may allow higher levels of AR expression under these conditions.
Issue Date: 29-Nov-2019
Date of Acceptance: 28-Nov-2019
URI: http://hdl.handle.net/10044/1/75425
DOI: 10.1530/EC-19-0340
ISSN: 2049-3614
Publisher: BioScientifica
Start Page: 9
End Page: 19
Journal / Book Title: Endocrine Connections
Volume: 9
Issue: 1
Copyright Statement: © 2019 The authors 2019. This accepted manuscript is available open access under a CC-BY-NC Licence (https://creativecommons.org/licenses/by-nc/4.0/deed.en_GB)
Keywords: Science & Technology
Life Sciences & Biomedicine
Endocrinology & Metabolism
prostate
cancer
bicalutamide
enzalutamide
anti-androgen
therapeutics
ANDROGEN RECEPTOR
EXPRESSION
MUTATIONS
MODEL
AR-V7
anti-androgen
bicalutamide
cancer
enzalutamide
prostate
therapeutics
Publication Status: Published
Online Publication Date: 2019-11-29
Appears in Collections:Central Faculty