Interaction between Non-Coding RNAs and Androgen Receptor with an Especial Focus on Prostate Cancer

The androgen receptor (AR) is a member of the nuclear receptor superfamily and has three functional domains, namely the N-terminal, DNA binding, and C-terminal domain. The N-terminal domain harbors potent transactivation functions, whereas the C-terminal domain binds to androgens and antiandrogens used to treat prostate cancer. AR has genomic activity being DNA binding-dependent or through interaction with other DNA-bound transcription factors, as well as a number of non-genomic, non-canonical functions, such as the activation of the ERK, AKT, and MAPK pathways. A bulk of evidence indicates that non-coding RNAs have functional interactions with AR. This type of interaction is implicated in the pathogenesis of human malignancies, particularly prostate cancer. In the current review, we summarize the available data on the role of microRNAs, long non-coding RNAs, and circular RNAs on the expression of AR and modulation of AR signaling, as well as the effects of AR on their expression. Recognition of the complicated interaction between non-coding RNAs and AR has practical importance in the design of novel treatment options, as well as modulation of response to conventional therapeutics.


Introduction
The androgen receptor (AR), alternatively named as NR3C4 (nuclear receptor subfamily 3, group C, member 4), is a nuclear receptor [1] that is activated by a number of androgens, such as testosterone and its more active form, dihydrotestosterone [2]. AR has three protein domains, namely the N-terminal transcriptional regulation, DNA binding, and C-terminal ligand binding domain [3]. After being activated by its ligands in the cytoplasm, AR is transferred into the nucleus, where it exerts its main DNA-binding-dependent functions [4]. In fact, AR is a cytoplasmic protein in the absence of its ligands associated with chaperone proteins, such as heat shock proteins and co-chaperones. Androgen binding to the AR results in conformational changes, dissociating it from chaperone proteins [4]. After translocation to the nucleus, the androgen/AR complex dimerizes and binds to androgen response elements (AREs), which are present in the AR target genes. This process is involved in the regulation of the expression of target genes [5]. In addition to this canonical route of action, the androgen/AR complex has other functions that are mediated through non-DNA-binding-dependent routes [6]. Modulation of activity of ERK, AKT, and MAPK pathways are examples of this kind of function [6][7][8].  Table 1. ( reduction or inhibition of, increased levels of, decreased levels of).

Indirectly Regulate AR Expression or AR Signal
On the other hand, a handful of miRNAs have been found to exert oncogenic roles in prostate cancer, through the regulation of transcription of AR expression or signaling. Following androgen deprivation therapy, hormone-sensitive prostate cancer can evolve to castration-resistant prostate cancer (CRPC). MiRNAs can contribute to this process. For instance, miR-221/-222 has been shown to be up-regulated in bone metastatic CRPC samples. In vitro studies have demonstrated that stable overexpression of miR-221 induces the androgen-independent growth of prostate cancer cells, by releasing these cells from androgen deprivation-related G1 arrest. The up-regulation of this miRNA in LNCaP has led to the reduction of expression of a subclass of androgen-responsive genes, without influencing the expression of AR or integrity of AR-androgen. MiR-221 has been found to regulate the expressions of HECTD2 and RAB1A, two genes being capable of the induction of CRPC phenotype in various prostate cancer cells. Further, the up-regulation of miR-221 has led to alterations in the expression levels of several cell cycle-related genes and the activation of EMT-related pathways. Taken together, it has been hypothesized that miR-221 has a major role in AR signaling reprogramming and the subsequent evolution of the CRPC phenotype [13].
Experiments in mice models have indicated the effect of surgical castration in the induction of an early upsurge in the serum levels of miR-125b. Moreover, bicalutamidemediated AR blocking has resulted in the prompt release of this miRNA into the media of cultured prostate cancer cells. NCOR2, as a corepressor of AR, has been shown to be targeted by miR-125b. Thus, miR-125b has been suggested as a key regulator of AR, which alters the efficacy of anti-androgen therapies [14].
MiR-96 is another oncogenic miRNA that can target a RARγ network to control AR signaling. Down-regulation of RARγ, a member of the nuclear receptor superfamily, has been shown to significantly affect the viability of prostate cancer cells and gene signature of these cells. A gene network, comprising of numerous RARγ target genes, such as

Indirectly Regu
On the other prostate cancer, th Following androg to castration-resist instance, miR-221/ ples. In vitro stud the androgen-inde androgen depriva led to the reductio influencing the ex regulate the expre tion of CRPC phe miR-221 has led to and the activation that miR-221 has a tion of the CRPC p  Table 1. ( reduction or inhibition of, increased levels of, decreased levels of).

Indirectly Regulate AR Expression or AR Signal
On the other hand, a handful of miRNAs have been found to exert oncogenic roles in prostate cancer, through the regulation of transcription of AR expression or signaling. Following androgen deprivation therapy, hormone-sensitive prostate cancer can evolve to castration-resistant prostate cancer (CRPC). MiRNAs can contribute to this process. For instance, miR-221/-222 has been shown to be up-regulated in bone metastatic CRPC samples. In vitro studies have demonstrated that stable overexpression of miR-221 induces the androgen-independent growth of prostate cancer cells, by releasing these cells from androgen deprivation-related G1 arrest. The up-regulation of this miRNA in LNCaP has led to the reduction of expression of a subclass of androgen-responsive genes, without influencing the expression of AR or integrity of AR-androgen. MiR-221 has been found to regulate the expressions of HECTD2 and RAB1A, two genes being capable of the induction of CRPC phenotype in various prostate cancer cells. Further, the up-regulation of miR-221 has led to alterations in the expression levels of several cell cycle-related genes and the activation of EMT-related pathways. Taken together, it has been hypothesized that miR-221 has a major role in AR signaling reprogramming and the subsequent evolution of the CRPC phenotype [13]. Experiments in mice models have indicated the effect of surgical castration in the induction of an early upsurge in the serum levels of miR-125b. Moreover, bicalutamidemediated AR blocking has resulted in the prompt release of this miRNA into the media of cultured prostate cancer cells. NCOR2, as a corepressor of AR, has been shown to be targeted by miR-125b. Thus, miR-125b has been suggested as a key regulator of AR, which alters the efficacy of anti-androgen therapies [14].
MiR-96 is another oncogenic miRNA that can target a RARγ network to control AR signaling. Down-regulation of RARγ, a member of the nuclear receptor superfamily, has been shown to significantly affect the viability of prostate cancer cells and gene signature of these cells. A gene network, comprising of numerous RARγ target genes, such as SOX15, has been found to be correlated with poor disease-free survival of prostate cancer patients [15].
MiR-541 is another oncogenic miRNA that can affect prostate cancer course through modulation of AR signaling. In fact, infiltrating CD4(+) T cells, which are associated with poor clinical outcomes in this type of cancer, can increase FGF11 levels. Up-regulation of this growth factor leads to increase levels of miR-541. The subsequent down-regulation of AR signaling regulates MMP9 levels, in favor of tumor metastasis [16]. Figure 2 shows the effects of oncogenic miRNAs in the progression of prostate cancer, through the modulation of AR signaling.
In addition to above-mentioned miRNAs, several miRNAs can directly or indirectly affect AR signaling by binding with 3 UTR, the coding region of AR, or influencing the levels of AR co-activators/co-repressors (Table 1).  miR-34a ↓ ↓ 3 UTR Notch-1 C4-2B, CWR22rv1, LNCaP, and VCaP ↓ proliferation and self-renewal capacity [56] miR-190a ↓ ↓ indirectly by regulating the activator of AR YB-1 LNCaP, C4-2, PC-3, DU-145, 22Rv1/mal nude mice ↓ proliferation and cell growth [57] patients [15]. MiR-541 is another oncogenic miRNA that can affect prostate cancer course through modulation of AR signaling. In fact, infiltrating CD4(+) T cells, which are associated with poor clinical outcomes in this type of cancer, can increase FGF11 levels. Up-regulation of this growth factor leads to increase levels of miR-541. The subsequent down-regulation of AR signaling regulates MMP9 levels, in favor of tumor metastasis [16]. Figure 2 shows the effects of oncogenic miRNAs in the progression of prostate cancer, through the modulation of AR signaling. In addition to above-mentioned miRNAs, several miRNAs can directly or indirectly affect AR signaling by binding with 3′ UTR, the coding region of AR, or influencing the levels of AR co-activators/co-repressors (Table 1).  Table 1. ( reduction or inhibition of, increased levels of, decreased levels of).

Indirectly Regulate AR Expression or AR Signal
On the other hand, a handful of miRNAs have been found to exert oncogenic roles in prostate cancer, through the regulation of transcription of AR expression or signaling. Following androgen deprivation therapy, hormone-sensitive prostate cancer can evolve to castration-resistant prostate cancer (CRPC). MiRNAs can contribute to this process. For instance, miR-221/-222 has been shown to be up-regulated in bone metastatic CRPC samples. In vitro studies have demonstrated that stable overexpression of miR-221 induces the androgen-independent growth of prostate cancer cells, by releasing these cells from androgen deprivation-related G1 arrest. The up-regulation of this miRNA in LNCaP has led to the reduction of expression of a subclass of androgen-responsive genes, without influencing the expression of AR or integrity of AR-androgen. MiR-221 has been found to regulate the expressions of HECTD2 and RAB1A, two genes being capable of the induction of CRPC phenotype in various prostate cancer cells. Further, the up-regulation of miR-221 has led to alterations in the expression levels of several cell cycle-related genes and the activation of EMT-related pathways. Taken together, it has been hypothesized that miR-221 has a major role in AR signaling reprogramming and the subsequent evolution of the CRPC phenotype [13]. decreased levels of).

Effects of miRNAs on AR in Other Different Cancer Types
In addition to prostate cancer, the effects of miRNAs on AR have been investigated in other cancer types ( Table 2). For instance, experiments in two AR-positive bladder cancer cell lines have shown that phenyl glucosamine can inactivate and degrade AR through the restoration of miR-449a expression. Lentivirus-mediated up-regulation of miR-449a has been shown to further suppress the proliferation of these cells via the induction of cell cycle arrest [58]. In addition, miR-9-5p has been identified as a suppressor of AR expression in breast cancer. A feedback loop has been recognized between these genes in breast cancer cells, in which androgen agonists of AR can increase expression of miR-9-5p. In fact, miR-9-5p can inhibit the proliferation of breast cancer cells in a manner independent from the estrogen receptor (ER) status of these cells. Moreover, miR-9-5p can decrease the activity of AR-downstream signals, even in the conditions that breast cancer cells are induced by AR-agonists [59].
In cervical cancer, the oncogenic miR-130a-3p has been found to target both ERα and AR. MiR-130a-3p silencing, ERα up-regulation, and AR up-regulation have suppressed proliferation and invasion of cervical cancer cells. Besides, antagomiR-130a could decrease tumor bulk in animal models. Taken together, miR-130a-3p has a possible role in the progression of cervical cancer, through the suppression of ERα and AR [60].

Regulation of AR Expression
PCGEM1 is a lncRNA with important roles in splicing events. This lncRNA has been found to interact with the splicing factors heterogeneous nuclear ribonucleoprotein (hnRNP) A1 and U2AF65. Experiments have shown correlation between PCGEM1 and AR3, a principal and clinically important alternatively spliced form of AR in prostate cancer. Besides, androgen deprivation leads to enhanced expression of PCGEM1 and its accretion in nuclear speckles. Androgen deprivation-induced PCGEM1 has a role in regulation of the competition between two splicing factors for AR pre-mRNA [65]. Another study has identified HORAS5 as a CRPC-promoting lncRNA through assessment of patientderived xenografts, clinical information with subsequent in vitro and in vivo confirmation studies. This lncRNA is a cytoplasmic lncRNA, which increases proliferation and viability of prostate cancer cells via sustaining AR activity even in androgen-depleted settings. Notably, HORAS5 silencing has reduced AR expression, as well as expression of oncogenic targets of AR, including KIAA0101. In clinical samples, up-regulation of HORAS5 has been associated with poor survival. Taken together, HORAS5 has been identified as targetable contributor in the induction of CRPC phenotype through maintaining oncogenic activity of AR [66]. Recent investigations identified a novel lncRNASAT1 as AR-interacting partner. The expression of this lncRNA is down-regulated in PCa tumor tissue compared to nontumor tissue indicating a tumor suppressive function. LncRNASAT1 is up-regulated by the treatment with supraphysiological androgen level (SAL) in PCa cells and human PCa tissue ex vivo and mediates the SAL-induced cellular senescence [67]. Further, it has been shown that lncRNASAT1 interacts with AR on chromatin level regulating AR transactivation and AR target gene expression [68]. Another study has identified a feed-forward regulatory circuit between AR and PlncRNA-1, which enhances progression of prostate cancer [69]. In addition, PCAL7 lncRNA is another lncRNA that enhances progression of this type of cancer through promoting AR signaling [70]. Figure 3 depicts the role of a number of lncRNAs in progression of prostate cancer through modulation of AR signaling.

Regulation of AR Activity as AR-Interacting Partner
Several other oncogenic lncRNAs have been found to regulate AR signaling. For instance, HOTAIR increases AR-mediated transcriptional program and induces CRPC phenotypes [71]. Moreover, MALAT1 has been shown to suppress cell cycle progression in this type of cancer through regulation of AR signaling [72]. LINC00844 is another lncRNA that affects migration and invasion of prostate cancer cells through modulation of this route [73].
In brief, lncRNAs can affect AR levels through interacting with AR on chromatin level, regulation of AR transactivation and modulation of AR target gene expression. Some lncRNAs can also regulate stability of AR transcripts and preventing its ubiquitination. Table 3 shows the effects of different lncRNAs on AR in prostate cancer.

Indirectly Regulate AR Expression or AR Sign
On the other hand, a handful of miRNAs h prostate cancer, through the regulation of tran Following androgen deprivation therapy, horm to castration-resistant prostate cancer (CRPC). M instance, miR-221/-222 has been shown to be up ples. In vitro studies have demonstrated that s the androgen-independent growth of prostate androgen deprivation-related G1 arrest. The up led to the reduction of expression of a subclas influencing the expression of AR or integrity of regulate the expressions of HECTD2 and RAB1 tion of CRPC phenotype in various prostate c miR-221 has led to alterations in the expressio and the activation of EMT-related pathways. T that miR-221 has a major role in AR signaling r tion of the CRPC phenotype [13].

Indirectly Regulate AR E
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Indirectly R
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Regulation of AR Activity as AR-Interacting Partner
Several other oncogenic lncRNAs have been found to regulate AR signaling. For instance, HOTAIR increases AR-mediated transcriptional program and induces CRPC phenotypes [71]. Moreover, MALAT1 has been shown to suppress cell cycle progression in this type of cancer through regulation of AR signaling [72]. LINC00844 is another lncRNA that affects migration and invasion of prostate cancer cells through modulation of this route [73].
In brief, lncRNAs can affect AR levels through interacting with AR on chromatin level, regulation of AR transactivation and modulation of AR target gene expression. Some lncRNAs can also regulate stability of AR transcripts and preventing its ubiquitination. Table 3 shows the effects of different lncRNAs on AR in prostate cancer. Table 3. Effects of different lncRNAs on AR in prostate cancer (ANCT: PCa: prostate cancer, DHT: dihydrotestosterone, CRPC: castration-resistant prostate cancer, ADPC: androgen-dependent prostate cancer, AD: androgen deprivation, DIM: 3,3 -Diindolylmethane, SAM: Synergistic activation mediator, LBD: ligand-binding domain, ↓: decrease in, ↑: increase in).

Effects of lnRNAs on AR in Other Different Cancer Types
The effects of lncRNAs on AR signaling have also been assessed in other types of cancers. In bladder cancer, XIST has been found to be up-regulated parallel with upregulation of AR. Over-expression of XIST and AR has been correlated with advanced TNM stage in this cancer. XIST silencing has decreased proliferation, invasion, and migratory potential of bladder cancer through modulation of AR signaling. Mechanistically, XIST suppresses expression of miR-124 through direct interaction. Besides, miR-124 has been shown to target 3 UTR of AR [92]. Another experiment in bladder cancer has shown over-expression of LINC00460. LINC00460 levels have been correlated with poor prognosis of these patients. LINC00460 silencing decreased proliferation of 5637 and T24 bladder cancer cells. Based on the observed down-regulation of AR in bladder urothelial cancer tissues, it has been suggested that LINC00460 might exert its oncogenic roles through modulation of AR expression [93]. LINC00278, SLNCR1, SARCC and HOTAIR are other lncRNAs whose effects on AR have been investigated in different cancer types (Table 4).

Effects of circRNAs on AR
circZMIZ1 has been shown to be over-expressed in plasma samples of patients with prostate cancer compared with those having benign prostatic hyperplasia (BPH). In vitro studies have shown that circZMIZ1 silencing inhibits cell proliferation and arrests cells at G1. Functionally, circZMIZ1 enhances expression of AR and its splice variant 7 (AR-V7) [100].
On the other hand, expression of cir-ITCH has been shown to be decreased in the tissues and cell lines of prostate cancer compared to corresponding controls. Up-regulation of cir-ITCH could suppress proliferation, migratory potential, and invasiveness of human prostate cancer cells. A reciprocal inhibitory effect has been found between this circRNA and miR-17. Several molecules within Wnt/β-catenin and PI3K/AKT/mTOR cascades have been found to be influenced by cir-ITCH. This circRNA could indirectly reduce expression of AR through regulating the coactivator of this nuclear factor [101]. hsa_circ_0004870 [102] and circRNA17 [103] are two other circRNAs that reduce AR-V7 levels through U2AF65 and miR-181c-5p mediated routes, respectively, thus enhancing efficacy of enzalutamide. Table 5 shows the effects of different circRNAs on AR in prostate cancer.

AR Responsive miRNA
AR has been found to regulate the expression of several ncRNAs. For instance, activated AR has been shown to increase the expression of miR-203 and decrease the expression of SRC kinase in prostate cancer model systems. MiR-203 has a direct interaction with the 3 UTR of SRC and affects its stability following AR activation. A reduction in AR-induced miR-203 levels has been associated with an increased growth and migration potential of prostate cancer cells. The dysregulation of the AR signaling in prostate cancer cells results in the over-expression of SRC and enhancement of metastatic ability of these cells [104].
Another experiment has shown that AR represses the expression of both miR-221/-222. The derepression of their expression after androgen deprivation has enhanced proliferation of prostate cancer cells via facilitating G1/S phase transition. Although this effect might be transient, it has a possible role in the evolution of CRPC. The restoration of AR activity via AR up-regulation could subsequently down-regulate miR-221/-222 [105]. MiR-182-5p is another AR-regulated miRNA that facilitates the progression of prostate cancer by targeting the ARRDC3/ITGB4 axis [106]. Another study has shown the effects of AR on the down-regulation of miR-1 expression and subsequent suppression of TCF7. This process has been shown to participate in the evolution of resistance to androgen deprivation in this type of cancer [107].
AR has been shown to differentially affect the metastasis of prostate and breast cancers, through distinctively changing vasculogenic mimicry (VM) formation. In fact, AR can enhance miR-525-5p transcription in prostate cancer, while decreasing its transcription in breast cancer by binding to different AREs in the precursor promoter of this miRNA. NFIX and HDAC2 have been identified as co-factors of AR in prostate and breast cancer cells, respectively [108]. Figure 4 shows the impact of AR on miRNAs expressions, in the context of prostate cancer.

AR Responsive lncRNA and circRNA
AR has also been shown to affect expression of several lncRNAs. For instance, LINC00304 is an androgen-responsive lncRNA that induces cell cycle transition and increases the proliferation of prostate cancer cells, through the regulation of CCNA1 [109]. Moreover, the androgen-associated up-regulation of POTEF-AS1 has been shown to affect apoptosis-associated pathways, in favor of prostate cancer cells survival [110]. On the other hand, the expression of PSLNR has been shown to be decreased by androgens. This lncRNA suppresses prostate cancer progression partly through regulation of the p53-dependent axis [111]. PART1, as another androgen-regulated lncRNA, can influence the toll-like receptor pathways in this type of cancer. The expression of PART1 has been induced in prostate cancer cells treated with 5α-dihydrotestosterone, indicating that this lncRNA is directly induced by androgen [112]. Figure 5 shows the effects of AR on lncRNAs in prostate cancer.  Table 6 ( reduction or inhibition of, increased levels of, decreased levels of).

AR Responsive lncRNA and circRNA
AR has also been shown to affect expression of several lncRNAs. For instance, LINC00304 is an androgen-responsive lncRNA that induces cell cycle transition and increases the proliferation of prostate cancer cells, through the regulation of CCNA1 [109]. Moreover, the androgen-associated up-regulation of POTEF-AS1 has been shown to affect apoptosis-associated pathways, in favor of prostate cancer cells survival [110]. On the other hand, the expression of PSLNR has been shown to be decreased by androgens. This lncRNA suppresses prostate cancer progression partly through regulation of the p53-dependent axis [111]. PART1, as another androgen-regulated lncRNA, can influence the tolllike receptor pathways in this type of cancer. The expression of PART1 has been induced in prostate cancer cells treated with 5α-dihydrotestosterone, indicating that this lncRNA is directly induced by androgen [112]. Figure 5 shows the effects of AR on lncRNAs in prostate cancer.  Table 1. ( reduction or inhibition of creased levels of, decreased levels of).

Indirectly Regulate AR Expression or AR Signal
On the other hand, a handful of miRNAs have been found to exert oncoge prostate cancer, through the regulation of transcription of AR expression or Following androgen deprivation therapy, hormone-sensitive prostate cancer to castration-resistant prostate cancer (CRPC). MiRNAs can contribute to this p instance, miR-221/-222 has been shown to be up-regulated in bone metastatic C ples. In vitro studies have demonstrated that stable overexpression of miR-2 the androgen-independent growth of prostate cancer cells, by releasing these androgen deprivation-related G1 arrest. The up-regulation of this miRNA in L led to the reduction of expression of a subclass of androgen-responsive gene influencing the expression of AR or integrity of AR-androgen. MiR-221 has bee regulate the expressions of HECTD2 and RAB1A, two genes being capable of tion of CRPC phenotype in various prostate cancer cells. Further, the up-reg miR-221 has led to alterations in the expression levels of several cell cycle-rel and the activation of EMT-related pathways. Taken together, it has been hyp that miR-221 has a major role in AR signaling reprogramming and the subsequ tion of the CRPC phenotype [13].  Table 1. ( red creased levels of, decreased levels of).

Indirectly Regulate AR Expression or AR Signal
On the other hand, a handful of miRNAs have been fo prostate cancer, through the regulation of transcription o Following androgen deprivation therapy, hormone-sensit to castration-resistant prostate cancer (CRPC). MiRNAs can instance, miR-221/-222 has been shown to be up-regulated ples. In vitro studies have demonstrated that stable overe the androgen-independent growth of prostate cancer cells androgen deprivation-related G1 arrest. The up-regulation led to the reduction of expression of a subclass of androg influencing the expression of AR or integrity of AR-androg regulate the expressions of HECTD2 and RAB1A, two gen tion of CRPC phenotype in various prostate cancer cells. miR-221 has led to alterations in the expression levels of s and the activation of EMT-related pathways. Taken toget that miR-221 has a major role in AR signaling reprogramm tion of the CRPC phenotype [13].

Indirectly Regulate AR Expression or AR Sig
On the other hand, a handful of miRNAs prostate cancer, through the regulation of tr Following androgen deprivation therapy, hor to castration-resistant prostate cancer (CRPC). instance, miR-221/-222 has been shown to be u ples. In vitro studies have demonstrated that the androgen-independent growth of prostat androgen deprivation-related G1 arrest. The u led to the reduction of expression of a subcla influencing the expression of AR or integrity o regulate the expressions of HECTD2 and RAB tion of CRPC phenotype in various prostate miR-221 has led to alterations in the expressi and the activation of EMT-related pathways. that miR-221 has a major role in AR signaling tion of the CRPC phenotype [13]. Other studies, in the context of prostate cancer, have identified AR-regulated miR-NAs and lncRNAs. Moreover, a number of circRNAs, such as circRNA-51217, circRNA-ARC1, and circZMIZ1, have been found to be influenced by AR signaling (Table 6). A recent study has identified more than 3000 androgen-responsive circRNAs, using a microarray technique. Notably, the expression of more than 1000 of these circRNAs has been consistent with the expression of their parent genes, suggesting that AR may modulate their expression at the transcriptional level [113].
In brief, the effect of AR on the expression of ncRNAs is mainly associated with its role as a transcription factor.

Indirectly Regulate AR Expression or AR Sign
On the other hand, a handful of miRNAs h prostate cancer, through the regulation of tran Following androgen deprivation therapy, horm to castration-resistant prostate cancer (CRPC). M

Indirectly Regulate AR E
On the other hand, a h prostate cancer, through th Following androgen depriv to castration-resistant prost

Indirectly R
On the ot prostate cance Following and Other studies, in the context of prostate cancer, have identified AR-regulated miRNAs and lncRNAs. Moreover, a number of circRNAs, such as circRNA-51217, circRNA-ARC1, and circZMIZ1, have been found to be influenced by AR signaling (Table 6). A recent study has identified more than 3000 androgen-responsive circRNAs, using a microarray technique. Notably, the expression of more than 1000 of these circRNAs has been consistent with the expression of their parent genes, suggesting that AR may modulate their expression at the transcriptional level [113].   In brief, the effect of AR on the expression of ncRNAs is mainly associated with its role as a transcription factor.
Effects of AR on expression of ncRNAs are also implicated in the pathoetiology of bladder, breast, liver, renal, and gastric cancers (Table 7). Yet, these effects are largely context-dependent. For instance, AR could reduce the expression of miR-21 in breast cancer [155], while inducing its expression in hepatocellular carcinoma [156].

Discussion
AR has an essential role in the pathogenesis of human cancers, particularly prostate cancer. Since it is required for the development of prostate cancer, androgen deprivation therapy is regarded as a treatment for this type of cancer. Thus, the identification of the regulatory mechanisms of AR signaling is important in the design of treatment options. The importance of this process is further highlighted by the fact that castration resistance might occur during the course of treatment, as a result of expression of constitutively active AR splice variants [172], whose expressions can be modulated by ncRNAs.
Integrative transcriptomic analyses of diverse cancer cell lines and tissues have resulted in the identification of several AR-interacting ncRNAs. In the current study, we have listed ncRNAs that affect expression of AR, as well as those being affected by AR. Notably, mutual interactions have been identified between AR and some of these non-coding transcripts. For instance, the expression of the lncRNA ARLNC1 has been shown to be enhanced by the AR protein. Conversely, ARLNC1 can increase the stability of the AR mRNA through RNA-RNA interaction [74].
AR-targeting miRNAs have been suggested as potent tumor suppressors in prostate cancer. However, a number of other miRNAs have also been found to induce CRPC, by changing the activity of AR signaling. Moreover, AR signaling can affect the expression of miRNAs through different mechanisms, including feedback loops.
Taken together, the data presented above indicates the complexity of the transcriptional regulation of miRNAs by AR and the effects of AR on them. Moreover, the interactions between ncRNAs and AR signaling can be context-dependent.