Imperial College London
Alternate

ProfessorCharlotteBevan

Faculty of Medicine, Department of Surgery & Cancer

Professor of Cancer Biology
 
 
 
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Contact

 

charlotte.bevan Website

 
 
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Assistant

 

Mrs Suzy Ford +44 (0)20 7594 2135

 
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Location

 

139ICTEM buildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Fletcher:2019:10.1038/s41388-019-0823-5,
author = {Fletcher, C and Sulpice, E and Combe, S and Shibakawa, A and Leach, D and Hamilton, MP and Chrysostomou, SL and Sharp, A and Welti, J and Yuan, W and Dart, D and Knight, E and Ning, J and Francis, JC and Kounatidou, EE and Gaughan, L and Swain, A and Lupold, SE and De, Bono JS and McGuire, SE and Gidrol, X and Bevan, C},
doi = {10.1038/s41388-019-0823-5},
journal = {Oncogene},
pages = {5700--5724},
title = {Androgen receptor-modulatory microRNAs provide insight into therapy resistance and therapeutic targets in advanced prostate cancer},
url = {http://dx.doi.org/10.1038/s41388-019-0823-5},
volume = {38},
year = {2019}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Androgen  receptor  (AR)  signalling  is  a  key  prostate  cancer  (PC)  driver,  even  inadvanced  ‘castrate-resistant’  disease  (CRPC).  To  systematically  identify  microRNAs  (miRs)  modulating  AR  activity  in  lethal disease, hormone-responsive and -resistant PC cells expressing a luciferase-based AR reporter were  transfected  with  a  miR  inhibitor  library;  78  inhibitors  significantly  altered  AR  activity.  Upon  validation,  miR-346,  miR-361-3p  and  miR-197  inhibitors  dramatically  reduced  AR  transcriptional  activity,  mRNA  and  protein  levels,  increased  apoptosis,  reduced  proliferation,  repressed  EMT,  inhibited PC migration and invasion, demonstrating additive effects with AR inhibition. Corresponding miRs  increased  AR  activity  through  a  novel  and  anti-dogmatic  mechanism  of  direct  association  with  AR 6.9kb 3’UTR and transcript stabilisation. In addition, miR-346 and miR-361-3p modulation altered levels  of  constitutively-active  AR  variants,  and  inhibited  variant-driven  PC  cell  proliferation,  so  may  contribute to persistent AR signalling in CRPC in the absence of circulating androgens. Pathway  analysis  of  AGO-PAR-CLIP-identified  miR  targets  revealed  roles  in  DNA  replication  and  repair, cell cycle, signal transduction and immune function. Silencing these targets, including tumour suppressors   ARHGDIA   and   TAGLN2,   phenocopied   miR   effects,   demonstrating   physiological   relevance.  MiR-346  additionally  upregulated  the  oncogene,  YWHAZ,  which  correlated  with  grade,  biochemical  relapse  and  metastasis  in  patients.  These  AR-modulatory  miRs  and  targets  correlated  with  AR  activity  in  patient  biopsies,  and  were  elevated  in  response  to  long-term  enzalutamide  treatment  of  patient-derived  CRPC  xenografts.  In  summary,  we  identified  miRs  that  modulate  AR  activity in PC and CRPC, via novel mechanisms, and may represent novel PC the
AU  - Fletcher,C
AU  - Sulpice,E
AU  - Combe,S
AU  - Shibakawa,A
AU  - Leach,D
AU  - Hamilton,MP
AU  - Chrysostomou,SL
AU  - Sharp,A
AU  - Welti,J
AU  - Yuan,W
AU  - Dart,D
AU  - Knight,E
AU  - Ning,J
AU  - Francis,JC
AU  - Kounatidou,EE
AU  - Gaughan,L
AU  - Swain,A
AU  - Lupold,SE
AU  - De,Bono JS
AU  - McGuire,SE
AU  - Gidrol,X
AU  - Bevan,C
DO  - 10.1038/s41388-019-0823-5
EP  - 5724
PY  - 2019///
SN  - 0950-9232
SP  - 5700
TI  - Androgen receptor-modulatory microRNAs provide insight into therapy resistance and therapeutic targets in advanced prostate cancer
T2  - Oncogene
UR  - http://dx.doi.org/10.1038/s41388-019-0823-5
UR  - http://hdl.handle.net/10044/1/68572
VL  - 38
ER  -
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