Androgen-regulated processing of the oncomir MiR-27a, which targets Prohibitin in prostate cancer
Androgen-regulated processing of the oncomir MiR-27a, which targets Prohibitin in prostate cancer
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DOI：
10.1093/hmg/dds139
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发表时间：
2012-07-15
影响因子：
3.5
通讯作者：
Bevan, Charlotte L.
中科院分区：
文献类型：
--
作者：
Fletcher, Claire E.;Dart, D. Alwyn;Bevan, Charlotte L.
微小RNA（miRs）在许多复杂的人类疾病的发展中起重要作用，并且可能具有肿瘤抑制或致癌（oncomir）特性。前列腺癌最初是一种雄激素驱动的疾病，即使在去势抵抗性肿瘤中，雄激素受体（AR）仍然是生长的关键驱动力。然而，AR介导的oncomiR通路仍有待阐明。我们证明了miR-27 a是前列腺癌中雄激素调节的oncomir，通过靶向肿瘤抑制因子和AR辅抑制因子Prohibitin（PHB）起作用。增加miR-27 a表达导致降低的PHBmRNA和蛋白水平，以及增加的AR靶基因表达和前列腺癌细胞生长。这涉及雄激素介导的miR调节的新机制，由此AR诱导miR-23 a27 a24 -2转录的瞬时增加，但更显著地加速miR-23 a27 a24 -2簇的加工。因此，雄激素在转录（通过AR与簇启动子结合）和转录后（加速miR-27加工成成熟形式）两方面调节miR-27 a表达。我们进一步表明，miR-27 a反义寡核苷酸，通过对抗mir-27 a的作用，在前列腺癌中具有治疗潜力。
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.