期刊
HUMAN MOLECULAR GENETICS
卷 21, 期 14, 页码 3112-3127出版社
OXFORD UNIV PRESS
DOI: 10.1093/hmg/dds139
关键词
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资金
- Medical Research Council of the United Kingdom
- Cancer Research UK
- Prostate Cancer Charity
- MRC [G0700915] Funding Source: UKRI
- Medical Research Council [G0700915] Funding Source: researchfish
- Prostate Cancer UK [PG10-25] Funding Source: researchfish
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.
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