title: Androgen-regulated processing of the oncomir miR-27a, which targets Prohibitin in prostate cancer.
abstract: MicroRNAs (miRs) play an important role in the development of many complex human diseases and may have tumour suppressor or oncogenic (oncomir) properties. Prostate cancer is initially an androgen-driven disease, and androgen receptor (AR) remains a key driver of growth even in castration-resistant tumours. However, AR-mediated oncomiR pathways remain to be elucidated. We demonstrate that miR-27a is an androgen-regulated oncomir in prostate cancer, acting via targeting the tumour suppressor and AR corepressor, Prohibitin (PHB). Increasing miR-27a expression results in reduced PHB mRNA and protein levels, and increased expression of AR target genes and prostate cancer cell growth. This involves a novel mechanism for androgen-mediated miR regulation, whereby AR induces a transient increase in miR-23a27a24-2 transcription, but more significantly accelerates processing of the primiR-23a27a24-2 cluster. Androgens therefore regulate miR-27a expression both transcriptionally (via AR binding to the cluster promoter) and post-transcriptionally (accelerating primiR processing to the mature form). We further show that a miR-27a anti-sense oligonucleotide, by opposing the effects of mir-27a, has therapeutic potential in prostate cancer.
authors.affiliation: Androgen Signalling Laboratory, Department of Surgery and Cancer, Imperial College London, London W12 0NN, UK.
authors.forename: Claire E
authors.initials: CE
authors.lastname: Fletcher
authors.forename: D Alwyn
authors.initials: DA
authors.lastname: Dart
authors.forename: Ailsa
authors.initials: A
authors.lastname: Sita-Lumsden
authors.forename: Helen
authors.initials: H
authors.lastname: Cheng
authors.forename: Paul S
authors.initials: PS
authors.lastname: Rennie
authors.forename: Charlotte L
authors.initials: CL
authors.lastname: Bevan
mesh_terms: D000728:Androgens / Q000378:metabolism*; D001483:Base Sequence; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D015513:Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D000091402:Prohibitins; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D012323:RNA Processing, Post-Transcriptional; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D000728:Androgens; C531388:MIRN27 microRNA, human; D035683:MicroRNAs; D015513:Oncogene Proteins; C000717328:PHB protein, human; D000091402:Prohibitins; D011944:Receptors, Androgen; D012097:Repressor Proteins