MicroRNAs Are Mediators of Androgen Action in Prostate and Muscle

Abstract

Androgen receptor (AR) function is critical for the development of male reproductive organs, muscle, bone and other tissues. Functionally impaired AR results in androgen insensitivity syndrome (AIS). The interaction between AR and microRNA (miR) signaling pathways was examined to understand the role of miRs in AR function. Reduction of androgen levels in Sprague-Dawley rats by castration inhibited the expression of a large set of miRs in prostate and muscle, which was reversed by treatment of castrated rats with 3 mg/day dihydrotestosterone (DHT) or selective androgen receptor modulators. Knockout of the miR processing enzyme, DICER, in LNCaP prostate cancer cells or tissue specifically in mice inhibited AR function leading to AIS. Since the only function of miRs is to bind to 3′ UTR and inhibit translation of target genes, androgens might induce miRs to inhibit repressors of AR function. In concordance, knock-down of DICER in LNCaP cells and in tissues in mice induced the expression of corepressors, NCoR and SMRT. These studies demonstrate a feedback loop between miRs, corepressors and AR and the imperative role of miRs in AR function in non-cancerous androgen-responsive tissues.

Interplay between steroid signalling and microRNAs: implications for hormone-dependent cancers

“…It was also hypothesised that reduced AR function upon loss of androgen-stimulated miR synthesis may be a result of androgen-regulated miR targeting of AR corepressors. Consistent with this, 75% of predicted NCoR or SMRTtargeting miRs were upregulated in the prostate by DHT, and Dicer siRNA treatment increased transcription of both NCoR and SMRT (Narayanan et al 2010). Taken together, these innovative data identify androgen-responsive tissuespecific miR profiles, and confirm androgen-upregulated miRs as vital mediators and enhancers of AR signalling through corepressor targeting (discussed also below).…”

“…The miR profile was not altered in the liver upon androgen treatment, but the levator ani muscle (which has an anabolic response to androgens) demonstrated an upregulated miR profile that differed significantly from that of the prostate, preferentially targeting components of the Raf/MEK/ERK signalling pathway (Narayanan et al 2010). Interestingly, Dicer siRNA completely inhibited dihydrotestosterone (DHT) induction of the wellcharacterised androgen-responsive gene PSA in LNCaP cells, and Dicer K/K mice developed androgen-insensitivity syndrome, indicating that androgen-regulated miRs are vital mediators of AR action in vivo (Narayanan et al 2010). It was also hypothesised that reduced AR function upon loss of androgen-stimulated miR synthesis may be a result of androgen-regulated miR targeting of AR corepressors.…”

“…Androgen regulation of miR expression Androgen-responsive tissues express distinct sets of miRs, as demonstrated by castration of Sprague-Dawley rats, which resulted in a dramatic reduction in a large subset of miRs in the prostate compared with intact animals, whilst treatment of castrated animals with androgen increased miR expression in a tissue-specific manner (Narayanan et al 2010). The miR profile was not altered in the liver upon androgen treatment, but the levator ani muscle (which has an anabolic response to androgens) demonstrated an upregulated miR profile that differed significantly from that of the prostate, preferentially targeting components of the Raf/MEK/ERK signalling pathway (Narayanan et al 2010).…”

Circulating microRNAs: macro-utility as markers of prostate cancer?

“…Given that the miRNA transcriptome is profoundly affected by androgen signaling in PCa (for review, see Coppola et al (2009)), it is not surprising that androgenic regulation of many of the circulating miRNAs described earlier has been documented (e.g. miR-141 and other miR-200 family members (Szczyrba et al 2010, Waltering et al 2010, miR-375 (Szczyrba et al 2010, Waltering et al 2010, miR-21 (Shi et al 2007, Ribas et al 2009, Narayanan et al 2010, and miR-221 (Sun et al 2009)). These observations provide important mechanistic information regarding the origins of these potential biomarkers, which may be critical for their effective clinical implementation.…”

MicroRNA: sex steroids, hormonal carcinogenesis, hormonal sensitivity of tumor tissue

“…Воздействие андрогенов на биогенез и функции микроРНК в рамках проблемы рака предстательной железы В норме андрогены регулируют экспрессию ми-кроРНК в ткани предстательной железы, благодаря чему контролируются многие структурные и функци-ональные особенности клеток простаты [25]. За послед-ние годы проведен ряд исследований изменения про-филя экспрессии микроРНК в клетках РПЖ [26][27][28], что позволило продемонстрировать роль микроРНК в опосредовании проканцерогенных эффектов андро-генов [29].…”