MicroRNAs as New Characters in the Plot between Epigenetics and Prostate Cancer

Abstract

Prostate cancer (PCA) still represents a leading cause of death. An increasing number of studies have documented that microRNAs (miRNAs), a subgroup of non-coding RNAs with gene regulatory functions, are differentially expressed in PCA respect to the normal tissue counterpart, suggesting their involvement in prostate carcinogenesis and dissemination. Interestingly, it has been shown that miRNAs undergo the same regulatory mechanisms than any other protein coding gene, including epigenetic regulation. In turn, miRNAs can also affect the expression of oncogenes and tumor suppressor genes by targeting effectors of the epigenetic machinery, therefore indirectly affecting the epigenetic controls on these genes. Among the genes that undergo this complex regulation, there is the androgen receptor (AR), a key therapeutic target for PCA. This review will focus on the role of epigenetically regulated and epigenetically regulating miRNAs in PCA and on the fine regulation of AR expression, as mediated by this miRNA–epigenetics interaction.

MicroRNAs that affect prostate cancer: emphasis on prostate cancer in African Americans

“…Epigenetic control of PCa involves specific miRNAs that are targets, i.e., epigenetically regulated (Table 5), and/or some miRNAs directly affect enzymes and other molecules involved in epigenetic control (Paone et al 2011). Examples of miRNAs that modulate epigenetic control in PCa include miRNA-101, which inhibits the oncogenetic protein enhancer of zeste homolog 2 (EZH2) and miRNA-449a, which down-regulates histone deacetylase 1 (Varambally et.…”

miR-22 and miR-29a Are Members of the Androgen Receptor Cistrome Modulating LAMC1 and Mcl-1 in Prostate Cancer

“…Numerous miRNA host genes as well as miRNAs promoters are epigenetically regulated in prostate cancer (36,66). For instance miR-193b and miR-34a are tightly controlled by promoter methylation in PCa (9).…”

“…Only recently, investigations have awakened attention to the interplay between AR and microRNAs (miRNAs or miRs) (5)(6)(7)(8). Like many protein-coding genes, miRNAs are under control of transcription factors as well as epigenetic mechanisms whose deregulation leads to a loss or gain of miRNA function with possible implications in tumorigenesis (9,10). miRNAs are short, noncoding, single-stranded RNAs that potentially regulate hundreds of mRNAs.…”

Fundamental Role of microRNAs in Androgen‐Dependent Male Reproductive Biology and Prostate Cancerogenesis

“…Surprisingly, miRNAs are also mediators of androgen action. 19,26,27 In PCa, AR can function in two opposite directions: 28 on one side, AR signaling is crucial for prostate and PCa cell survival; 29 however, its activation can also limit cell proliferation and mediate apoptotic induction under specific circumstances, 28,29 like in conditions of genotoxic stress, when AR is fundamental for p53 activation and for the subsequent induction of apoptosis. Even though androgens increase the expression of a large set of miRNAs, clinically only a few miRNAs mediate androgen action in prostate.…”

“…25 Epigenetic regulation of androgen receptivity is also modulated by miRNA While in some cases, AR is not functional because of genetic mutations, it has been found in almost 40% of PCa patients (like in DU145 cell line) to be silenced by promoter hypermethylation. 19,26,27 In PCa, AR can function in two opposite directions: 28 on one side, AR signaling is crucial for prostate and PCa cell survival; 29 however, its activation can also limit cell proliferation and mediate apoptotic induction under specific circumstances, 28,29 like in conditions of genotoxic stress, when AR is fundamental for p53 activation and for the subsequent induction of apoptosis. 30,31 A new study has found at least 71 miRNAs affecting the AR expression in PCa cell lines, 13 of them directly binding to and regulating its 6-kb extended 3′-UTR.…”