Interplay between the androgen receptor signaling axis and microRNAs in prostate cancer

Abstract

The androgen receptor (AR) is a ligand-activated transcription factor that drives prostate cancer. Since therapies that target the AR are the mainstay treatment for men with metastatic disease, it is essential to understand the molecular mechanisms underlying oncogenic AR signaling in the prostate. miRNAs are small, non-coding regulators of gene expression that play a key role in prostate cancer and are increasingly recognized as targets or modulators of the AR signaling axis. In this review, we examine the regulation of AR signaling by miRNAs and vice versa and discuss how this interplay influences prostate cancer growth, metastasis and resistance to therapy. Finally, we explore the potential clinical applications of miRNAs implicated in the regulation of AR signaling in this prevalent hormone-driven disease.

MicroRNAs as Guardians of the Prostate: Those Who Stand before Cancer. What Do We Really Know about the Role of microRNAs in Prostate Biology?

“…Several candidate miRNAs have been determined to target AR directly [52,168,182,183]. As we have mentioned earlier, miR-30 family members are some of the most prominent in prostate cancer cells that can directly target AR.…”

“…Therefore, understanding the altered expression of miRNAs that target AR and are AR-regulated can help to understand the development of resistance to therapy. Since a recent review article has dealt with the subject comprehensively [182], we would only like to highlight a few aspects of the relationship between miRNAs and AR.…”

“…On the other hand, AR signaling influences the expression of a set of miRNAs including miR-148, -182, -22, -29, and -21 [182]. Interestingly, in CRPC characterized by reduced AR signaling, one can observe the paradoxical increased expression of AR-induced miRNAs such as miR-182/183 and the reduction of AR-inhibited miRNAs such as miR-99 and miR-100.…”

Coordinated AR and microRNA regulation in prostate cancer

“…Let-7c indirectly represses AR activity by targeting c-Myc, which acts as a transcription factor for the AR gene [ 65 , 66 ]; (B) AR mRNA—miRs target AR directly through binding to microRNA response elements in its transcript. Most microRNAs target the 3′UTR [ 4 , 24 , 31 , [38] , [39] , [40] , [41] , [42] , [43] , 45 , 46 ], but interactions with the coding region and 5′UTR have also been reported [ 4 , 56 ]; (C) AR-mediated transcription of target genes—miRs modulate AR indirectly by targeting cofactors, regulators or effectors of AR activity [ 19 , 63 , 64 ]; (D) AR competitive endogenous RNAs (ceRNAs) —AR is regulated by ceRNAs containing microRNA response elements (MREs) for AR-targeting miRs. For example, PlncRNA-1 protects AR from miR-mediated repression.…”

“…The intricate multi-step biogenesis of miRs (with additional complexity afforded by non-canonical pathways that bypass Drosha or Dicer [ 29 ], and by post-translational modifications to pathway components [ 30 ]) provides opportunities for AR-mediated fine-tuning of their synthesis at many stages. Indeed, mounting evidence supports a complex, responsive and dynamic network of bi-directional interactions between AR and miRs at all steps of biogenesis and during target gene regulation [ 31 , 32 ]. For example, Dicer siRNA completely inhibited dihydrotestosterone (DHT) induction of the well-characterised androgen responsive gene, prostate-specific antigen (PSA) in LNCaP cells, and Dicer −/− mice developed androgen-insensitivity syndrome, indicating that androgen-regulated miRs are vital mediators of AR action in vivo [ 33 ].…”