Androgen receptor-modulatory microRNAs provide insight into therapy resistance and therapeutic targets in advanced prostate cancer

Claire E. Fletcher, Eric Sulpice, Stephanie Combe, Akifumi Shibakawa, Damien A. Leach, Mark P. Hamilton, Stelios L. Chrysostomou, Adam Sharp, Jon Welti, Wei Yuan, Dafydd A. Dart, Eleanor Knight, Jian Ning, Jeffrey C. Francis, Evangelia E. Kounatidou, Luke Gaughan, Amanda Swain, Shawn Lupold, Johann S. de Bono, Sean E. McGuireXavier Gidrol, Charlotte L. Bevan

Research output: Contribution to journalArticle

Abstract

Androgen receptor (AR) signalling is a key prostate cancer (PC) driver, even in advanced ‘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 markedly reduced AR transcriptional activity, mRNA and protein levels, increased apoptosis, reduced proliferation, repressed EMT, and 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 6.9 kb 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 therapeutic targets.

Original languageEnglish (US)
JournalOncogene
DOIs
StatePublished - Jan 1 2019

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Androgen Receptors
MicroRNAs
Prostatic Neoplasms
Therapeutics
Luciferases
DNA Replication
Oncogenes
Heterografts
DNA Repair
Androgens
Libraries
Signal Transduction
Cell Cycle
Cell Proliferation
Hormones

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Androgen receptor-modulatory microRNAs provide insight into therapy resistance and therapeutic targets in advanced prostate cancer. / Fletcher, Claire E.; Sulpice, Eric; Combe, Stephanie; Shibakawa, Akifumi; Leach, Damien A.; Hamilton, Mark P.; Chrysostomou, Stelios L.; Sharp, Adam; Welti, Jon; Yuan, Wei; Dart, Dafydd A.; Knight, Eleanor; Ning, Jian; Francis, Jeffrey C.; Kounatidou, Evangelia E.; Gaughan, Luke; Swain, Amanda; Lupold, Shawn; de Bono, Johann S.; McGuire, Sean E.; Gidrol, Xavier; Bevan, Charlotte L.

In: Oncogene, 01.01.2019.

Research output: Contribution to journalArticle

Fletcher, CE, Sulpice, E, Combe, S, Shibakawa, A, Leach, DA, Hamilton, MP, Chrysostomou, SL, Sharp, A, Welti, J, Yuan, W, Dart, DA, Knight, E, Ning, J, Francis, JC, Kounatidou, EE, Gaughan, L, Swain, A, Lupold, S, de Bono, JS, McGuire, SE, Gidrol, X & Bevan, CL 2019, 'Androgen receptor-modulatory microRNAs provide insight into therapy resistance and therapeutic targets in advanced prostate cancer', Oncogene. https://doi.org/10.1038/s41388-019-0823-5
Fletcher, Claire E. ; Sulpice, Eric ; Combe, Stephanie ; Shibakawa, Akifumi ; Leach, Damien A. ; Hamilton, Mark P. ; Chrysostomou, Stelios L. ; Sharp, Adam ; Welti, Jon ; Yuan, Wei ; Dart, Dafydd A. ; Knight, Eleanor ; Ning, Jian ; Francis, Jeffrey C. ; Kounatidou, Evangelia E. ; Gaughan, Luke ; Swain, Amanda ; Lupold, Shawn ; de Bono, Johann S. ; McGuire, Sean E. ; Gidrol, Xavier ; Bevan, Charlotte L. / Androgen receptor-modulatory microRNAs provide insight into therapy resistance and therapeutic targets in advanced prostate cancer. In: Oncogene. 2019.
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abstract = "Androgen receptor (AR) signalling is a key prostate cancer (PC) driver, even in advanced ‘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 markedly reduced AR transcriptional activity, mRNA and protein levels, increased apoptosis, reduced proliferation, repressed EMT, and 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 6.9 kb 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 therapeutic targets.",
author = "Fletcher, {Claire E.} and Eric Sulpice and Stephanie Combe and Akifumi Shibakawa and Leach, {Damien A.} and Hamilton, {Mark P.} and Chrysostomou, {Stelios L.} and Adam Sharp and Jon Welti and Wei Yuan and Dart, {Dafydd A.} and Eleanor Knight and Jian Ning and Francis, {Jeffrey C.} and Kounatidou, {Evangelia E.} and Luke Gaughan and Amanda Swain and Shawn Lupold and {de Bono}, {Johann S.} and McGuire, {Sean E.} and Xavier Gidrol and Bevan, {Charlotte L.}",
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AU - Fletcher, Claire E.

AU - Sulpice, Eric

AU - Combe, Stephanie

AU - Shibakawa, Akifumi

AU - Leach, Damien A.

AU - Hamilton, Mark P.

AU - Chrysostomou, Stelios L.

AU - Sharp, Adam

AU - Welti, Jon

AU - Yuan, Wei

AU - Dart, Dafydd A.

AU - Knight, Eleanor

AU - Ning, Jian

AU - Francis, Jeffrey C.

AU - Kounatidou, Evangelia E.

AU - Gaughan, Luke

AU - Swain, Amanda

AU - Lupold, Shawn

AU - de Bono, Johann S.

AU - McGuire, Sean E.

AU - Gidrol, Xavier

AU - Bevan, Charlotte L.

PY - 2019/1/1

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N2 - Androgen receptor (AR) signalling is a key prostate cancer (PC) driver, even in advanced ‘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 markedly reduced AR transcriptional activity, mRNA and protein levels, increased apoptosis, reduced proliferation, repressed EMT, and 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 6.9 kb 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 therapeutic targets.

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