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dc.contributor.authorFletcher, CE
dc.contributor.authorDeng, L
dc.contributor.authorOrafidiya, F
dc.contributor.authorYuan, W
dc.contributor.authorLorentzen, MPGS
dc.contributor.authorCyran, OW
dc.contributor.authorVarela-Carver, A
dc.contributor.authorConstantin, TA
dc.contributor.authorLeach, DA
dc.contributor.authorDobbs, FM
dc.contributor.authorFigueiredo, I
dc.contributor.authorGurel, B
dc.contributor.authorParkes, E
dc.contributor.authorBogdan, D
dc.contributor.authorPereira, RR
dc.contributor.authorZhao, SG
dc.contributor.authorNeeb, A
dc.contributor.authorIssa, F
dc.contributor.authorHester, J
dc.contributor.authorKudo, H
dc.contributor.authorLiu, Y
dc.contributor.authorPhilippou, Y
dc.contributor.authorBristow, R
dc.contributor.authorKnudsen, K
dc.contributor.authorBryant, RJ
dc.contributor.authorFeng, FY
dc.contributor.authorReed, SH
dc.contributor.authorMills, IG
dc.contributor.authorde Bono, J
dc.contributor.authorBevan, CL
dc.identifier.citationMolecular cancer, 2022, 21 (1), pp. 82 - ?en
dc.description.abstract<h4>Background</h4>miR-346 was identified as an activator of Androgen Receptor (AR) signalling that associates with DNA damage response (DDR)-linked transcripts in prostate cancer (PC). We sought to delineate the impact of miR-346 on DNA damage, and its potential as a therapeutic agent.<h4>Methods</h4>RNA-IP, RNA-seq, RNA-ISH, DNA fibre assays, in vivo xenograft studies and bioinformatics approaches were used alongside a novel method for amplification-free, single nucleotide-resolution genome-wide mapping of DNA breaks (INDUCE-seq).<h4>Results</h4>miR-346 induces rapid and extensive DNA damage in PC cells - the first report of microRNA-induced DNA damage. Mechanistically, this is achieved through transcriptional hyperactivation, R-loop formation and replication stress, leading to checkpoint activation and cell cycle arrest. miR-346 also interacts with genome-protective lncRNA NORAD to disrupt its interaction with PUM2, leading to PUM2 stabilisation and its increased turnover of DNA damage response (DDR) transcripts. Confirming clinical relevance, NORAD expression and activity strongly correlate with poor PC clinical outcomes and increased DDR in biopsy RNA-seq studies. In contrast, miR-346 is associated with improved PC survival. INDUCE-seq reveals that miR-346-induced DSBs occur preferentially at binding sites of the most highly-transcriptionally active transcription factors in PC cells, including c-Myc, FOXA1, HOXB13, NKX3.1, and importantly, AR, resulting in target transcript downregulation. Further, RNA-seq reveals widespread miR-346 and shNORAD dysregulation of DNA damage, replication and cell cycle processes. NORAD drives target-directed miR decay (TDMD) of miR-346 as a novel genome protection mechanism: NORAD silencing increases mature miR-346 levels by several thousand-fold, and WT but not TDMD-mutant NORAD rescues miR-346-induced DNA damage. Importantly, miR-346 sensitises PC cells to DNA-damaging drugs including PARP inhibitor and chemotherapy, and induces tumour regression as a monotherapy in vivo, indicating that targeting miR-346:NORAD balance is a valid therapeutic strategy.<h4>Conclusions</h4>A balancing act between miR-346 and NORAD regulates DNA damage and repair in PC. miR-346 may be particularly effective as a therapeutic in the context of decreased NORAD observed in advanced PC, and in transcriptionally-hyperactive cancer cells.en_US
dc.format.extent82 - ?en_US
dc.subjectProstatic Neoplasmsen_US
dc.subjectDNA Damageen_US
dc.subjectRNA-Binding Proteinsen_US
dc.subjectTranscription Factorsen_US
dc.subjectCell Cycleen_US
dc.subjectRNA, Long Noncodingen_US
dc.titleA non-coding RNA balancing act: miR-346-induced DNA damage is limited by the long non-coding RNA NORAD in prostate cancer.en
dc.typeJournal Article
dc.relation.isPartOfMolecular canceren_US
pubs.notesNot knownen_US
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Cancer Biomarkers
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Cancer Biomarkers
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Prostate Cancer Targeted Therapy Group
pubs.organisational-group/ICR/Students/PhD and MPhil
pubs.organisational-group/ICR/Students/PhD and MPhil/18/19 Starting Cohort
pubs.embargo.termsNot knownen_US
icr.researchteamCancer Biomarkers
icr.researchteamProstate Cancer Targeted Therapy Group
dc.contributor.icrauthorDe Bono, Johannen_US
dc.contributor.icrauthorGurel, Boraen_US

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