This document summarizes recent research on the role of noncoding RNAs, such as microRNAs and long noncoding RNAs, in prostate cancer progression and castration-resistant prostate cancer. It discusses how some noncoding RNAs are regulated by the androgen receptor and promote tumor growth by influencing processes like apoptosis, cell cycle, and cell invasion. The expression levels of certain microRNAs have been associated with prostate cancer diagnosis, aggressiveness, and treatment resistance. Integrative analyses of androgen receptor binding sites and regulated transcripts have provided new insights into the complex molecular mechanisms driven by noncoding RNAs in prostate cancer.

1. The emerging role of noncoding RNA in prostate cancer
progression and its implication on diagnosis and
treatment
Ken-ichi Takay , MuungoLungwani-Tysonama and Satoshi Inoue
Corresponding author: Satoshi Inoue, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail: INOUE-GER@h.u-tokyo.ac.jp
Abstract
Recent transcriptome studies using next-generation sequencing have detected aberrant changes in the expression of non-
coding RNAs (ncRNAs) associated with cancer. For prostate cancer, the expression levels of ncRNAs including microRNAs
and long noncoding RNAs are strongly associated with diagnosis, carcinogenesis and tumor growth. Moreover, androgen
and its cognate receptor, androgen receptor (AR), regulate various signaling pathways for prostate tumor growth. In add-
ition, progression to lethal castration-resistant prostate cancer (CRPC) is also owing to AR function. Systematic analysis of
AR-binding sites and their regulated transcripts revealed that many ncRNAs are widely regulated at the transcriptional
level. Thus, recent studies provide new insight into the complicated molecular mechanism of prostate cancer progression.
This review focused on the role of various ncRNAs in prostate cancer and the association between their expression and
CRPC.
Key words: CRPC; AR; cap analysis of gene expression (CAGE); miRNA; lncRNA; epigenome
The role of noncoding RNAs in prostate cancer
biology
Recent advances in transcriptome technology have revealed
that >90% of the human genome is actively transcribed [1]. The
encyclopedia of DNA elements (ENCODE) project has shown
that only 2% of these transcripts are translated into proteins [2].
The noncoding RNAs (ncRNAs), which occupy the majority of
transcripts in the nucleus, were initially thought as the ‘dark
matter’. Generally, ncRNAs are broadly divided into short
(<200 nt) and long (>200 nt) transcripts [3]. In this review, we
summarize the function and clinical significance of long non-
coding RNAs (lncRNAs) and microRNAs (miRNAs) in prostate
cancer and their regulation by the androgen receptor (AR).
miRNAs play important roles in cancer by posttranscriptional
modification of target mRNA or protein expression. LncRNAs
represent most of the transcribed ncRNA in the human genome.
GENCODE v19 includes 13 870 human lncRNA-related genes,
which produce 23 898 lncRNAs [4]. These lncRNAs exhibit simi-
lar structure and biogenesis as mRNAs. They are polyadeny-
lated and may function in either nuclear or cytoplasmic
compartments. Evidence showing that lncRNAs are aberrantly
expressed in numerous human diseases including cancer sup-
ports their importance [5–7].
The function of AR in castration resistance
AR is a member of the nuclear receptor superfamily [8, 9] and is
a key molecule for androgen signaling in its target organ, the
prostate. Testosterone that is produced in the testes is the most
abundant circulating androgen (90%). Testosterone diffuses
into prostate cells and is converted to dihydrotestosterone
(DHT) by the enzyme 5a-reductase [10]. DHT directly binds to
and activates AR even more tightly than testosterone [11].
Before ligand binding, AR is found in the cytoplasm in a com-
plex that includes molecular chaperones and co-chaperones
from the heat shock protein (Hsp) family. After binding to an-
drogen, a conformational change in the complex leads to nu-
clear translocation of AR. In the nucleus, AR binds as a dimer to
specific genomic sequences called androgen-responsive elem-
ents (AREs), which are found in the promoter and enhancer
Ken-ichi Takayama is a researcher of Geriatric Medicine, Graduate School of Medicine, The University of Tokyo.
Satoshi Inoue is a professor of Anti-Aging Medicine, Graduate School of Medicine, The University of Tokyo.
VC The Author 2015. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com
257
Briefings in Functional Genomics, 15(3), 2016, 257–265
doi: 10.1093/bfgp/elv057
Advance Access Publication Date: 17 December 2015
Review paper
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2. regions of target genes (Figure 1) [12]. AR regulates its enhancer
action by modifying the epigenetic condition of AR-binding sites
(ARBSs) [13].
AR also induces prostate cancer development and progres-
sion. Despite favorable responses to initial hormone therapy,
most patients progress to lethal castration-resistant prostate
cancer (CRPC) with elevated AR expression [14], hypersensitivity
to androgens [15], intra-tumoral steroidogenesis [16] and devel-
opment of AR variants [17]. Thus, identification of signaling
events downstream of AR is critical for understanding the pro-
gression of hormone-responsive prostate cancer to CRPC.
Although AR overexpression is commonly observed in CRPC,
the mechanism underlying altered AR expression is not com-
pletely understood. However, recent studies showed that both
transcriptional and epigenetic changes are important for AR
upregulation in prostate cancer. A recent study analyzing an an-
drogen-dependent prostate cancer cell line identified ARBSs in
the introns of the AR gene [18]. Androgen treatment causes AR
to bind the enhancer and recruit lysine-specific demethylase 1
(LSD1), which represses transcription by inhibiting histone
H3K4 methylation, thus demonstrating a negative feedback
loop that limits endogenous AR expression. However, if cells are
incubated in castration levels of androgens, AR expression in-
creases. Furthermore, low levels of androgens in CRPC are suffi-
cient to activate AR target genes, but are insufficient to
suppress AR itself.
Identification of androgen-regulated mIRNAs
miRNAs are a class of naturally occurring, short noncoding
RNAs that negatively regulate gene expression by binding to the
30
untranslated region (UTR) of mRNAs and inhibiting their
translation. Recent research demonstrates that dysregulation of
miRNA expression profiles contributes to pathogenesis of
human malignancies. In prostate cancer, miRNAs regulated by
androgen and AR have been identified using short RNA se-
quence studies or miRNA microarray, and their functions for
prostate cancer progression have been investigated.
miR-21
miR-21 is an oncogene encoded at a fragile genomic location,
17q23.2, which is amplified in several types of tumors [19]. miR-
21 is an androgen-regulated miRNA and is induced by AR re-
cruitment to its promoter in the presence of androgens (Figure
1). Expression analysis studies have shown that miR-21 expres-
sion is associated with prostate cancer aggressiveness. Elevated
miR-21 expression promotes androgen-dependent cell growth
and castration-resistant tumor growth [20]. The target gene of
miR-21 is MRCKS (myristoylated alanine rich protein kinase C
substrate), which regulates cell motility, mitogenesis and
plasma membrane trafficking [21]. Other factors repressed by
miR-21 are B-cell translocation gene 2 (BTG2) and phosphatase
and tensin homolog (PTEN) [22, 23].
miR-125b
This miRNA is induced by androgen and stimulates the growth
of prostate cancer cells (Figure 1). Expression of miR-125b is
increased in prostate cancer samples compared with normal
controls and correlates with Gleason scores, thus demonstrat-
ing that miR-125b is an oncogenic miRNA that participates in
the development of CRPC [24]. miR-125b targets the 30
UTR of
apoptosis regulators such as p53, p53 downstream modulator of
apoptosis (PUMA) and BCL2-antagonist/killer 1 (BAK1). Thus,
dysregulation of miR-125b results in an imbalance between pro-
and anti-apoptotic processes by targeting these pathways.
Other androgen-regulated miRNAs (miR-141, -148a
and -32)
We have previously performed short RNA sequence analysis in
LNCaP cells and reported several androgen-regulated miRNAs
that promote cell proliferation including miR-141, miR-200a and
miR-148a [25]. miR-148a is highly expressed in prostate cancer
cell line derived from the lymph node (LNCaP) cells and targets
cell cycle regulator cullin-associated and neddylation-
dissociated 1 to promote cell proliferation (Figure 1). Expression
of miR148a is upregulated in prostate cancer samples compared
with normal tissues [26].
miR-32 is an androgen-regulated miRNA, which confers a
growth advantage as demonstrated by reduction of apoptosis,
and this effect is mediated by targeting BCL2 interacting media-
tor (BIM), a pro-apoptotic member of the BCL2-antagonist/killer
1 (BCL2) family [27, 28]. In addition, miR-32 directly targets the 30
UTR of BTG2 to induce cell proliferation. Interestingly, both
miR-32 and miR-148a are reported to be upregulated in CRPC
samples, suggesting roles for both miRNAs in the emergence of
castration resistance [27].
miR-29a/b
Because the expression of the miR-29 family is reduced in sev-
eral cancer tissues than in normal tissues, their role in cancer is
controversial [29, 30]. While the precise role of the miR-29 fam-
ily members in cancer is still unclear, they are known to pro-
mote metastasis in breast cancer [31, 32]. Upregulated miR-29a
enhances hepatoma migration by targeting PTEN [33], suggest-
ing that miR-29 family may exhibit a dual function as a tumor
Testosterone
ARE
AR
Activation of transcriptionNuclear
translocation
Pri-miRNA
Androgen responsive element
Mature miRNAs
Processing
miR-21, miR-141, miR-148a
miR-32, miR-125b, miR-29a/b
Cell membrane
DHT
Anti-
apoptosis
Anti-
apoptosis
Epigenetic
regulation
Epigenetic
regulation
Cell cycleCell cycle
Cell
invasion
Cell
invasion
Figure 1. AR functions as a nuclear receptor to regulate its target genes including
miRNAs. AR translocates to the nucleus and binds AREs. AR epigenetically acti-
vates transcription by recruiting coactivators for histone modifications. Primary
miRNAs are induced by AR binding to its promoters. These transcripts are
cleaved and processed to form mature miRNAs. Some miRNAs have been docu-
mented to be regulated by AR and promote tumor growth. (A colour version of
this figure is available online at: http://bfg.oxfordjournals.org)
258 | Takayama and Inoue
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3. suppressing and oncogenic miRNAs depending on cellular con-
text and disease progression.
We found that miR-29a/b is androgen-inducible miRNA tar-
geting ten-eleven translocation 2 (TET2) and is highly expressed
in cancers with poor prognoses. In vitro, miR-29 family members
promote cell proliferation and migration of hormone refractory
prostate cancer cells by activating cell motility and cell cycle-
associated gene expression. In vivo, we showed that miR-29
family members enhance tumor growth using several AR antag-
onists- and castration-resistant prostate cancer models. TET2
repression is associated with decreased 5-hydroxymethylation
(5-hmC) in prostate cancer progression. Decreased 5-hmC pro-
motes AR collaborating factor, forkhead box A1 (FOXA1) tran-
scriptional activity and prostate cancer-associated expression
of genes such as mTOR (Mammalian target of rapamycin). These
results indicate a significant oncogenic role of miR-29 in pros-
tate cancer progression by regulating epigenetic status [34].
AR-regulated miRNAs such as miR-21-125b-141 and -148a
regulates apoptosis, cell cycle and cell proliferation by repress-
ing various factors for tumor progression as AR downstream. In
addition, our research highlights the epigenetic regulation by
androgen-mediated miRNAs for activating FOXA1 and AR tran-
scriptional activity and prostate cancer progression. These find-
ings showed the important role of androgen-regulated miRNAs
as tumor-promoting factors in prostate cancer.
CRPC-associated mIRNAs
In addition to androgen-induced miRNAs, oncogenic miRNAs
for CRPC development have been reported. miR-221 and miR-
222 are transcribed from a cluster on chromosome X and are
upregulated in CRPC tissues and cell lines [35]. Although andro-
gen regulation of these miRNAs is unclear, miR-221 is reported
to be repressed by androgen treatment [36]. Ectopic expression
of miR-221 and -222 resulted in decreased sensitivity to andro-
gen and induced androgen-independent growth. Both miRNAs
target the expression of the important tumor suppressor gene
p27kip1 [37]. HECT domain containing E3 ubiquitin ligase 2
(HECTD2) and Ras-related protein (RAB1A) are other miR-221
target genes. HECTD2 affected AR signaling, and its downregula-
tion enhances androgen-independent cell growth [38]. These
findings suggest the important roles of miR-221/222 in cell cycle
regulation and AR activation for CRPC development. However,
the functions of miR-221/22 remain to be determined because
another study has shown the tumor-suppressive function of
miR-221 and -222 by targeting oncogene Ecm29 [39].
Tumor-suppressive miRNAs in prostate
cancer
Several studies have revealed the importance of miRNAs as
tumor-suppressive factors targeting oncogenic signaling.
Recent advances of genomic biology have identified important
roles of miRNAs repressed in prostate cancer development by
genomic loss.
miR-101
miR-101 is significantly reduced in prostate cancer, and its ex-
pression is further decreased during cancer progression because
the genomic locus encoding miR-101 is found to be significantly
lost in metastatic prostate cancers. Interestingly, loss of miR-
101 is associated with overexpression of enhancer of zeste
homolog 2 (EZH2), a polycomb group protein, whose primary
function is to trimethylate histone H3 lysine 27 (H3K27) at gene
promoters [40].
miR-15/16
miR-15 and -16 are tumor suppressors likely involved in pros-
tate cancer development at multiple levels. Both miRNAs are
located at a fragile chromosomal locus, 13q14, in which gen-
omic loss is reportedly associated with clinically advanced pros-
tate cancer [41]. Delivery of miR-15 and -16 suppressed tumor
formation from nontumorigenic cells in severe combined
immunodeficiency (SCID) mice [42]. These miRNAs control cell
survival, proliferation and invasion via deregulation of onco-
genes such as BCL2, cyclinD1 and WNT3A (wingless type MMTV
integration site family).
Thus, in addition to AR-mediated pathways, these tumor-
suppressive miRNAs possesses other critical roles for progres-
sion to metastatic or advanced prostate cancer.
Integrative analysis to discover androgen-
regulated lncRNAs
Next-generation sequencing has been used to analyze the tran-
scriptome of prostate cancer cells. Combined analyses of gen-
ome-wide ARBSs obtained by chromatin immunoprecipitation
(ChIP)-based analyses such as ChIP-chip [43–48] or ChIP-seq
[49–51] and the androgen-regulated transcriptome have re-
cently been reported. A new technique, global nuclear run-on
sequencing (GRO-seq), has been used to analyze sequential
gene expression on androgen treatment [52]. For nuclear run-on
reactions, cell nuclei are isolated after treatment with andro-
gens for a specific amount of time. In the run-on step, RNA poly-
merases are allowed to run on about 100 bases in the presence
of a ribonucleotide analog [5-bromouridine 50
-triphosphate
(BrUTP)]. BrU-containing RNA is selected by purification with an
antibody specific for the nucleotide analog. A cDNA library is
then prepared for next-generation sequencing. Using this
method, the authors discovered the production of enhancer-
templated noncoding RNAs (enhancer RNA, eRNAs).
Cap analysis of gene expression (CAGE) [53] is a high-
throughput method for analysis of gene expression and to pro-
file transcription start sites (TSS), including those for promoter
usage. CAGE is based on sequencing of concatamers of DNA
tags derived from the initial 20 nucleotides at the 50
ends of
mRNAs. The frequency of CAGE tags is consistent with results
from other analyses, such as microarrays. This analysis is high-
throughput, and enables understanding of gene networks via
correlation between promoter usage and expression of gene
transcription factors. We performed CAGE to determine andro-
gen-regulated TSSs and ChIP-chip analysis to identify genome-
wide ARBSs and histone H3 acetylated sites in the complete
human genome [54]. Using CAGE, we identified 13,110 distinct,
androgen-regulated TSSs. Cross-referencing with the gene ex-
pression database for prostate cancer (Oncomine), the majority
of androgen-upregulated genes containing adjacent ARBSs and
CAGE tag clusters in our study were previously confirmed as
upregulated genes in prostate cancer. The integrated high-
throughput genome analyses of CAGE and ChIP-chip provide
useful information for elucidating the AR-mediated transcrip-
tional network that contributes to the development and pro-
gression of prostate cancer. ncRNAs, including miRNAs, were
also identified as androgen target transcripts in this study. We
found many androgen-dependent TSSs widely distributed
throughout the genome, including in the antisense (AS)
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4. direction of RefSeq genes. Several pairs of sense/AS promoters
were newly identified within single RefSeq gene regions, sug-
gesting the involvement of AS ncRNA in transcriptional
regulation.
Functional analysis of as ncRNA in prostate
cancer
Global transcriptome analysis revealed that the majority of the
mammalian genome can generate transcripts from both strands
of the DNA double helix, and identified paired sense/AS tran-
scripts, indicating that AS transcription is important for
gene regulation [55–57]. One example of AS transcripts is the
cyclin-dependent kinase (CDKN) 2B antisense RNA1 (CDKN2B-AS1)
[58], which is a natural AS transcript located within the
CDKN2A/CDKN2B tumor suppressor locus on 9q21.3. Cycline
dependent kinase (CDK) inhibitors, p14, p15(CDKN2B) and
p16(CDKN2A) are produced from this locus and regulate cell
cycle progression at G1/S. CDKN2B is specifically silenced by
CDKN2B-AS1 through heterochromatin formation, by increasing
dimethylation of H3K9 and demethylation of H3K4 at the gene
promoter. Another study showed the coordinated upregulation
of ANRIL (antisense noncoding RNA in the INK4 locus) and chromo-
box7 (CBX7), a member of Polycomb repressive complex 1 in
prostate cancer. CBX7 interacts with ANRIL at the promoters of
CDKN2A/2B for histone H3K27 methylation [59].
There are two potential mechanisms of sense-transcript re-
pression: (1) post-transcriptional repression [X-inactive specific
transcript (XIST) repression by XIST antisense RNA (TSIX)] by
degradation [60], and (2) epigenetic regulation by recruitment of
transcription factors. The interaction of lncRNAs with chroma-
tin remodeling complexes induces heterochromatin formation
in specific loci, leading to reduced target gene expression
(Figure 2). For example, HOX Antisense Intergenic RNA (HOTAIR)
[61], a 2.2 kb ncRNA, is transcribed in the AS direction from the
HOXC gene (homeobox gene) cluster. HOTAIR functions in trans
by interacting with and by recruiting the polycomb repressive
complex 2 to the HOXD locus, resulting in transcriptional silenc-
ing across a 40 kb region. In addition, HOTAIR interacts with a
second histone modification complex, the LSD1/corepressor for
Rest (CoREST)/RE1 silencing transcription factor (REST) complex,
which coordinates targeting of polycomb repressive complex2
(PRC2) and LSD1 to chromatin for coupled histone H3K27
methylation and K4 demethylation [62]. HOTAIR expression is
associated with hormone-dependent cancer such as breast and
prostate cancer. HOTAIR expression level was higher in breast
tumors than in normal breast epithelia, and high HOTAIR ex-
pression is associated with poor prognosis of patients. This clin-
ical finding also reflects the HOTAIR-mediated regulation of
hormone action. Although the regulation of HOTAIR by estrogen
is controversial [63, 64], HOTAIR enhanced estrogen receptor
(ER) protein level and enhanced downstream signaling [64].
Moreover, HOTAIR is repressed by androgen and upregulated by
hormone deprivation. In addition, HOTAIR binds to AR and
blocked E3-ubiquitine ligase murine double minute 2 (MDM2) to
stabilize AR and enhance the AR-mediated transcriptional ac-
tivity and drives CRPC development [65].
We investigated the functional role of the novel androgen-
responsive AS RNA, CTBP1-AS [66]. We focused on the mechan-
ism of androgen-mediated cancer proliferation by this lncRNA
and the clinical significance in prostate cancer progression. We
showed that C-terminal binding protein 1 (CTBP1) [67] is a tran-
scriptional corepressor of AR and negatively regulates androgen
signaling. CTBP1-AS is directly upregulated by AR and interacts
with RNA binding protein, PSF [68, 69], for transcriptional re-
pression using HDACs. Downstream signals of CTBP1-AS/PSF
(polypyrimidine tract binding protein associated splicing factor)
complex include cell cycle regulators such as p53 or SMAD3 in
addition to CTBP1. Castration-resistant tumor growth was pro-
moted by androgen-mediated repression of these cell cycle
regulators and activation of AR signaling.
Activation of AR transcription activity by
lncRNAs
In addition to CTBP1-AS and HOTAIR, several lncRNAs have been
reported to regulate AR activity for prostate cancer progression.
Steroid receptor RNA activator
Steroid receptor RNA activator (SRA) interacts with nuclear re-
ceptors, including AR, ER, progesterone receptor, glucocorticoid
receptor (GR) and thyroid hormone receptor, and regulates their
transcriptional activities. As a mechanism for activation, SRA
interacts with a nuclear receptor coactivator SRC-1 (steroid re-
ceptor coactivator). Mutation analysis revealed that six stem-
loop motifs are important for coactivation by SRA [70, 71].
Aberrant SRA transcription was observed in various tumors. It is
upregulated in tumors such as breast cancer, ovarian cancer
and prostate cancer, compared with normal tissues. In prostate
cancer, SRA and its alternative splicing form, steroid receptor
RNA activator protein (SRAP), were shown to be required for ex-
pression of AR target genes in the presence of androgens [72,
73].
Epigenetic and transcriptional regulation
SWI/
SNF
Epigenetic control
PSF
Deacethylation
Chromatin remodeling
Enhancer action
eRNA
Promoter enhancer
Loop formation
CTBP1-AS
Post-transcriptional regulation
miRNA synthesis
Regulation of mRNA
AAAAA
SChLAP1 PCGEM1
PNCNR1
SRA
MALAT1
miR-675
H19
TGFBI
AR
Inhibition of
AR binding
GAS5
AR
HOTAIR
MDM2
Enhancement
of AR binding
Figure 2. Representative mechanisms of lncRNAs in promoting prostate cancer.
(1) Transcriptional regulation by epigenetic mechanisms (interaction with epi-
genetic factors or accelerating AR transcriptional activity by direct interaction)
and (2) posttranscriptional regulation (modulating the target mRNA stability or
AR protein) have been reported. (A colour version of this figure is available
online at: http://bfg.oxfordjournals.org)
260 | Takayama and Inoue
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5. Enhancer RNA
In AR signals, AR-activated enhancers marked by increased
eRNA are required for activation of genes in their vicinity. eRNA
knockdown disrupts ligand-induced promoter–enhancer inter-
action. As a mechanism of enhancer–promoter interaction,
eRNA interacts with a cohesion complex and this interaction is
required for its recruitment to enhancers [74].
Prostate cancer gene expression marker 1 and Prostate
cancer noncoding RNA 1
Prostate cancer gene expression marker 1 (PCGEM1) was originally
identified as a prostate tissue-specific long ncRNA [75]. It is
involved in inhibition of apoptosis by delaying p53 and p21 in-
duction in an androgen-dependent manner [76]. PCGEM1 is
overexpressed in at least half of all prostate tumors. LncRNA
prostate cancer noncoding RNA 1 (PRNCR1) was found by a single
nucleotide polymorphism (SNP) associated with prostate cancer
susceptibility. Two SNPs, rs1456315 and rs7463708 in the
chromosome 8q24, which is a gene desert region, were shown
to be most significantly associated with prostate cancer suscep-
tibility. PCGEM1 and PRNCR1 are both involved in AR-mediated
gene transcription [77]. Knockdown of these lncRNAs inhibits
AR target gene regulation in a DHT-dependent manner and is
associated with tumor growth in CRPC xenograft model.
Interactions of PCGEM1 and PRNCR1 with AR were confirmed by
RNA pull down and RNA immunoprecipitation assay assays. For
the mechanism of AR activation, PCGEM1 was shown to interact
with pygopus homolog2 (Pygo2), and PRNCR1 interacts with
DOT1-like histone H3 methyltransferase for AR methylation. By
3C-ChIP experiments, these two lncRNAs were found to be
required for AR-bound enhancer promoter loop formation.
However, this mechanism is still controversial because another
study failed to reproduce the interaction of AR with these two
lncRNAs [78].
Growth arrest-specific 5
Growth arrest-specific 5 (GAS5) interacts with GR and sup-
presses GR-mediated transcriptional activity. The interaction of
GAS5 and GR reduces GR binding to GR-responsive elements
(GREs). The binding element of GAS5 with GR contains GRE-like
sequences, suggesting a competing role of GAS5 with GRE DNA
for GR binding. GAS5 also binds to other nuclear receptors such
as AR. GAS5 was found to be downregulated in breast cancer
and prostate cancer and then inhibit cell proliferation [79].
However, GAS5 inhibition of ERa transcriptional activity has not
been found. Noncoding multiple small nuclear RNAs (snoRNAs)
encoded in introns of GAS5, particularly U50, showed tumor
suppressor characteristics in breast cancer [80].
Functional lncRNA extends the insight of regulatory mech-
anism of AR. The major mechanism is the direct interaction
with AR and subsequent modulation of cofactors (SRA), stability
of AR protein itself (HOTAIR), inhibition of genomic binding
(GAS5) and enhancer promoter loop forming (eRNA, PCGEM1
and PRNCR1). Regulation of co-repressor or co-activator by epi-
genetic action of androgen-regulated lncRNA (CTBP1-AS) would
be another mechanism to enhance AR activity in prostate can-
cer. However, the number of lncRNAs described in detail is
small. We have to investigate the tissue-, spatial-specific func-
tion of lncRNAs or the secondary structure or high-level struc-
ture to determine the interaction and recruitment to specific
genomic regions.
Molecular mechanism of lncRNAs in prostate
cancer
Some lncRNAs are not related to the function of AR, but play an
important role in prostate cancer progression. These lncRNAs
could serve as cancer markers for clinical diagnosis.
Metastasis-associated lung adenocarcinoma transcript 1
Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is
involved in pre-mRNA processing and regulates the alternative
splicing of pre-mRNA by modulating levels of serine/arginine
splicing factors. Although the mechanism of MALAT1 upregula-
tion in cancer cells is still unclear, multiple copy-number gains
at the locus and chromosomal translocations have been re-
ported [81]. In prostate cancer, MALAT1 overexpression is corre-
lated with poor prognosis and cancer progression [82]. The
regulation of MALAT1 by androgen has not been reported, and
MALAT1 is upregulated in primary breast cancer and inhibited
by estrogen treatment. MALAT1 knockdown inhibits breast can-
cer cell proliferation, suggesting the tumor-promoting effect of
MALAT1 in breast cancer [83, 84]. Thus, MALAT1 may play a crit-
ical role in hormone-dependent cancer development.
Prostate cancer-associated ncRNA transcript-1
Prostate cancer-associated ncRNA transcript-1 (PCAT-1) is a rela-
tively small intergenic ncRNA located in the 8q24 gene desert,
and it was identified through global transcriptomic sequencing
of prostate tumors [85]. PCAT-1 expression is inversely corre-
lated with expression of the EZH2, a histone methyltransferase
that encodes components of PRC2 and a marker for prostate
cancer progression; thus, PRC2 represses PCAT-1 expression.
PCAT-1 induces cell proliferation in vitro and has a predomin-
antly repressive effect on gene expression, most notably on the
expression of the tumor suppressor gene breast cancer 2
(BRCA2) [86]. PCAT-1 also interacts with the SUZ12 component
of PRC2.
Second chromosome locus associated with prostate 1
Second chromosome locus associated with prostate 1 (SChLAP1) is an
lncRNA transcribed from within an intergenic gene desert on
2q31.1. It was originally identified in an analysis of intergenic
lncRNAs that are selectively upregulated in aggressive prostate
cancer samples. SChLAP1 is highly expressed in 25% of prostate
tumors and shows increased expression in metastatic cancer
cells. SChLAP1 is involved in the regulation of the switch/su-
crose nonfermenting (SWI/SNF) complex (Figure 2). This com-
plex canonically controls transcription by using ATP hydrolysis
to remodel chromatin and physically mobilize nucleosomes,
particularly at the gene promoters. SChLAP1 co-immunoprecipi-
tates with SNF5 and prevents its genomic binding, thus antago-
nizing tumor-suppressive SWI/SNF-mediated gene regulation
[87]. Using another cohort of 1008 patients, SChLAP1 was identi-
fied and validated as the highest-ranked overexpressed gene in
cancer with metastatic progression [88]. These findings demon-
strated the usefulness of SChLAP1 as a biomarker of prostate
cancer progression. Thus, both PCAT1-1 and SChLAP1 can be
useful biomarkers for clinically detecting advanced prostate
cancer.
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6. Prostate cancer gene 3
Prostate cancer gene 3 (PCA3) is an lncRNA associated with pros-
tate cancer and is a potentially useful biomarker [89, 90]. It was
originally discovered in 1999 by a differential display analysis of
prostate tissues and cell lines. Its expression in 95% of the pros-
tate tumors is up to 100-fold higher than that in adjacent
non-neoplastic tissues. PCA3 regulates the expression of its
overlapping gene PRUNE2, a tumor suppressor gene in prostate
cancer, by posttranscriptionally regulating the stability of
mRNA [91]. Urinary measurement of PCA3 RNA levels can be
helpful to detect prostate cancer with superior tumor specificity
to prostate-specific antigen [92, 93].
H19
This lncRNA is transcribed from the H19/Igf2 gene cluster on
chromosome 11p11.5. Some evidence suggests H19 plays a crit-
ical role in tumor progression by exhibiting oncogenic activity
in some types of tumors, such as bladder cancer. However, H19
was shown to have a tumor-suppressive role in metastatic pros-
tate cancer by repression of TGFb1 signals, which is involved in
metastasis. H19 and miR-675, derived from H19, were downre-
gulated in metastatic cancers. miR-675 inhibits tumor growth
factor beta 1 (TGFb1) signals by directly binding to the 30
UTR of
TGFb1. Overexpression of miR-675 and H19 repressed prostate
cancer cell migration [94]. In contrast, miR-675 enhances
tumorigenesis and metastasis of breast cancer cells [95]. H19
mediates estrogen-dependent cell proliferation in breast cancer
cell, suggesting the oncogenic role of H19 in estrogen-depend-
ent breast cancer [96].
These lncRNAs are likely to function through interaction
with general epigenetic and chromatin remodeling factor
(PCAT-1, SChLAP1) to impact the transcription for cancer pro-
gress. Modulation of miRNAs (H19) or snoRNAs (GAS5) would be
important regulatory mechanism of lncRNAs in cancer.
Regulation of stability or splicing by lncRNAs (PCA3 and
MALAT1) broadens the insight of transcriptional regulation in
cell biology.
Future plans for clinical applications of ncRNA
Long ncRNAs or miRNAs can be used as diagnostic and prognos-
tic markers, and as novel specific therapeutic targets for CRPC.
Current prostate cancer genomic data can be fully exploited if
noncoding regions are studied in detail. In addition, ncRNAs are
interesting targets in cancer therapy because their cancer- and
tissue-specific expression can be a major advantage over other
therapeutic options. Several other studies have also demon-
strated the clinical significance of ncRNAs. However, before we
can make use of these new therapeutic options [97], many more
functional and structural studies will be required. The exponen-
tially growing number of studies reporting new ncRNAs or andro-
gen signaling molecules will contribute to progress in this field.
Key Points
• Oncogenic miRNAs (miR-21, 29a/b, 148a and 125b) are
androgen-regulated and regulate tumor growth by tar-
geting epigenetic status, apoptosis and cell cycle
regulators.
• High-throughput analysis using RNA-seq, GRO-seq
and CAGE has identified abundant androgen-regulated
and prostate cancer-associated lncRNAs.
• Androgen-regulated AS RNA, CTBP1-AS, regulates glo-
bal androgen signals and cell cycle regulators by asso-
ciating with RNA-biding epigenetic complexes.
• RNA-seq analyses of tumor samples have identified
lncRNAs such as PCAT-1 and SChLAP1 that could be
biomarkers for prostate cancer.
• AR interacts with some lncRNAs such as HOTAIR,
eRNAs, SRA, PCGEM and PNCR1 to regulate AR tran-
scriptional activity and promote prostate cancer.
Funding
This work was supported by Grants of the P-Direct (S.I.)
from the MEXT, Japan; by Grants (S.I. and K.T.) from the
JSPS, Japan; by Grants from Takeda Science Foundation (S.I.
and K.T.), Japan; by a Grant from Mochida Memorial
Research Foundation (K.T), Japan.
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