Skip to main content

Androgen receptor and gene network: Micromechanics reassemble the signaling machinery of TMPRSS2-ERG positive prostate cancer cells

Abstract

Prostate cancer is a gland tumor in the male reproductive system. It is a multifaceted and genomically complex disease. Transmembrane protease, serine 2 and v-ets erythroblastosis virus E26 homolog (TMPRSS2-ERG) gene fusions are the common molecular signature of prostate cancer. Although tremendous advances have been made in unraveling various facets of TMPRSS2-ERG-positive prostate cancer, many research findings must be sequentially collected and re-interpreted. It is important to understand the activation or repression of target genes and proteins in response to various stimuli and the assembly in signal transduction in TMPRSS2-ERG fusion-positive prostate cancer cells. Accordingly, we divide this multi-component review ofprostate cancer cells into several segments: 1) The role of TMPRSS2-ERG fusion in genomic instability and methylated regulation in prostate cancer and normal cells; 2) Signal transduction cascades in TMPRSS2-ERG fusion-positive prostate cancer; 3) Overexpressed genes in TMPRSS2-ERG fusion-positive prostate cancer cells; 4) miRNA mediated regulation of the androgen receptor (AR) and its associated protein network; 5) Quantitative control of ERG in prostate cancer cells; 6) TMPRSS2-ERG encoded protein targeting; In conclusion, we provide a detailed understanding of TMPRSS2-ERG fusion related information in prostate cancer development to provide a rationale for exploring TMPRSS2-ERG fusion-mediated molecular network machinery.

Introduction

Multiple molecular signaling pathways overlap, integrate and promote the progression of intraepithelial neoplasia and metastasis. Accumulating evidence has shown that genomic rearrangements play a vital role in regulating differentiation, cell proliferation and invasive growth of prostate cancers[1]. Recently, the fusion genes from the ETS transcription factors like v-ets erythroblastosis virus E26 homolog (avian) (ERG) were identified and reportedly upregulated in an androgen-dependent manner[2]. The fusion gene-positive cells may transform their phenotypes from indolent and local nodules to a more aggressive and less differentiated type of prostate cancer cells[1]. This review mainly focuses on the representation of signaling cascades and targeting gene network in fusion positive prostate cancer cells. In addition, it also provides information about broadening landscape of over-expressed androgen receptor (AR) through loss of control of miRNA subsets.

Genomic instability

Previous findings have linked aberrant genomic rearrangements to tumor development. During tumorigenesis, malignant cells not only carry somatic mutations from the founder cell but also contain other acquired mutations from daughter cells. Moreover, DNA damage repair ignaling involved in androgen treated prostate cancer cells. Androgen treatment can activate Ataxia telangiectasia mutated (ATM) and Ataxia telangiectasia and Rad3 related (ATR) in the immortalized normal prostate epithelial HPr-1 AR cells. Moreover, knockdown of ATM and ATR in HPr-1 AR cells can induce transmembrane protease, serine 2 and ERG (TMPRSS2-ERG) fusion transcript[3]. Additionally, androgen ablation can downregulate the expression of TMPRSS2:ERG[4]. AR facilitated recruitment of activation-induced cytidine deaminase (AID) and LINE-1 repeat-encoded ORF2 endonuclease for TMPRSS2:ERG rearrangements[5]. Certain hints have emerged suggesting that androgen signaling induced co-recruitment of AR and TOP2B topoisomerase (DNA) II beta 180 kDa (TOP2B) at genomic breakpoints of TMPRSS2-ERG, where TOP2B mediated double stranded breaks and triggered this rearrangements[6]. Mechanistically it was shown that AR bound to multiple intronic regions near break sites in TMPRSS2 and ERG, suggesting that AR mediated juxtapositioning of DNA breaks was essential for recombination and these genomic rearrangements appears to be nonrandom[7, 8].

ERG-overexpressing cancer cells demonstrated higher single-strand break repair (SSBR) rate and leaded to radiation resistance[9]. It is intriguing to note that knockdown of PARP1 poly (ADP-ribose) polymerase 1 (PARP1) in ERG-positive prostate cancer PC3 and DU145 cells may resensitize radioresistant cancer cells. Targeted inhibition of a DNA SSBR protein (XRCC1) by siRNA in ERG-overexpressing cancer cells may impair ERG induced SSBR and partially resensitize the cell radoresistance. In a xenograft model, PARP1 inhibitor ABT-888 can recover the ERG conferring radioresistance[9].

Prostate cancer and precursor lesions

Moreover, it is becoming clear that high-grade prostatic intraepithelial neoplasia (HGPIN) is a precursor of some prostate carcinomas, and thus is often characterized by TMPRSS2-ERG fusion gene[10–12]. HGPIN is composed of benign prostatic acini lined by cells with a malignant phenotype, and prostate carcinomas may have zones of HGPIN from which glands harboring carcinoma originate. It is worth noting, prostates with carcinoma have more of these hallmark foci than those without carcinoma. Prostate glands with extensive HGPIN have more multifocal carcinomas at the same time. Development of HGPIN lesions occurs predominantly in the peripheral zone of the prostate, which is believed to be the primary site of origin for most adenocarcinomas. This is in accordance with the fact that HGPIN lesions may initially be polyclonal proliferations, with cells with TMPRSS2-ERG fusion being diluted in a pool of cells which do not feature this alteration. The HGPIN lesion may eventually be dominated by the clone with the TMPRSS2-ERG fusion as a result of clonal expansion, as evidenced by the analysis of ERG overexpression in a subset of HGPIN lesions.

TMPRSS2-ERG fusion in prostate normal and cancer cells

New research results were reported that the TMPRSS2-ERG fusion appears in late stage and in benign hyperplasia[13] as well as in the normal margin of prostate tumors[14–18]. For example, the detection of TMPRSS2-ERG fusion transcript were reported to 73% of primary prostate tumor samples and 43% samples taken from non-malignant tissues[19]. Accordingly, the levels of TMPRSS2-ERG fusion transcript are correlated with the status of prostate cells in normal or malignancy. In addition, it is noted that different established prostate cancer cell lines may have different statuses for TMPRSS2-ERG. For example, the human prostate cancer VCaP cells are TMPRSS2-ERG positive with wild type AR, whereas human prostate cancer LNCaP cells are TMPRSS2-ERG negative with mutated AR.

The methylation may play an important role in regulating the TMPRSS2-ERG fusion. For example, it was reported that fusion negative tumors are heavily methylated as compared to fusion positive samples in terms of methylated DNA immunoprecipitation sequencing[20]. The enhancer of zeste homolog 2 (Drosophila) (EZH2), a histone methyltransferase, was upregulated in fusion negative prostate tumor and controlled by miR-26a. Additionally, SPINK1 overexpression has a tight correlation with small deletions of 6q15- and 5q21 in ERG negative prostate cancers[21]. Loss of CDKN1B/p27Kip1 expression was observed in subset of ERG-negative, low-grade tumors[22]. In contrast, FOXP2 forkhead box P2 (FOXP2) and nibrin (NBN or NBS1) are overexpressed in fusion negative prostate cancer cells[23, 24].

Accordingly, These results suggested that the TMPRSS2:ERG fusion is nonrandom in genomic level but may be random in cell type level. In the next section we will briefly discuss difference of TMPRSS2-ERG positive and negative prostate cancer cells and how gene networks are regulated in fusion positive cancer cells.

Signal transduction cascades in fusion-positive prostate cancer

Prostate cancer is developed through a series of specific genetic alterations. It requires initial clonal expansion, genomic instability, inactivation of tumor suppressor genes, overexpression of oncogenes, and disruption of the spatial-temporal behavior of signaling cascades[25].

With the landmark identification of a recurrent gene fusion event on chromosome 21 between the TMPRSS2 and ERG genes, prostate cancers are now categorized as "fusion-positive" and "fusion-negative"[12]. Following genomic rearrangement, the expression of transcription factor ERG may be regulated through the promoter of the androgen-responsive gene TMPRSS2. For example, TMPRSS2-ERG fusion products can bind to the ERG locus and result in an overexpression of wild-type ERG. Interestingly, polycomb proteins can modulate the hypermethylation of ERG promoters in prostate cancer cells, which also indicates the ERG gene is a hotspot of DNA methylation, especially for tumors with DNA methylation of ERG[26].

Targeted inhibition of TMPRSS2-ERG in VCaP cells resulted in notably downregulated wild-type ERG, whereas stable transfection of TMPRSS2-ERG in the TMPRSS2-ERG deficient PC3 cells resulted in upregulation of wild-type ERG transcript. This experimental data provides a direct evidence that ERG is overexpressed in fusion positive prostate cancer cells[27]. There are divergent pieces of evidence suggesting regulation of AR by ERG. For example, ERG signaling did not exert repressive effect on AR expression of ERG-negative and moderate ERG expressing prostate cancer cells[28]. In contrast, another study indicated ERG can bind to AR and suppress AR expression in prostate cancer VCaP cells[29]. Additionally, androgen treatment can initiate TMPRSS2-ERG fusion in both prostate normal and tumor cells[30]. The in vivo growth of xenografts was propagated by serial transplantation on male nude mice to explore a correlation between TMPRSS2-ERG fusion and androgen. It was observed that all androgen-dependent xenografts presented an overexpression of TMPRSS2-ERG. Moreover, although xenografts carrying AR-negative tumors harbor a TMPRSS2-ERG fusion gene, the fusion gene is not expressed[31].

TMPRSS2-ERG fusion-positive prostate cancer cells show increased expression of several proliferation-related genes than do fusion-negative prostate cancer cells. More importantly, TMPRSS2-ERG fusion redirects these genes under androgen regulation, while chemical castration and anti-androgens downregulate one-half of these genes, and decrease the transcriptome differences between fusion-positive and -negative cases[32]. In addition, targeted inhibition of the enzymes responsible for conversion of testosterone to dihydrotestosterone (DHT) in TMPRSS2-ERG fusion-positive VCaP cells substantially decreased proliferation and invasion. In vivo studies confirmed that the combined treatment of dutasteride (a 5α-reductase inhibitor) and anti-androgen bicalutamide extensively repressed the tumor burden in xenograft animal studies[33].

Various signal transduction cascades were deregulated in fusion-positive prostate cancer patients. Overrepresented genes from the WNT and transforming growth factor, beta 1 (TGFB1)/bone morphogenetic protein (BMP) transduction cascades were validated[34] in the public gene expression database of prostate tumors[35]. In addition, various tumor suppressors including p53, phosphatase and tensin homolog (PTEN), breast cancer 1, early onset (BRCA1) and BRCA2 are frequently truncated as a result of genomic rearrangements in prostate cancer progression. Other studies have indicated that genomic rearrangements resulted in repression of tumor suppressor genes[36].

Peroxiredoxins 3 (PRDX3) and PRDX4 have been found to be upregulated in prostate cancer tissue and impact the cell growth of prostate tumors. Furthermore, upregulation of PRDX3 and PRDX4 is negatively correlated with the level of the TMPRSS2-ERG gene fusion[37]. Chromatin immunoprecipitation (ChIP) performed in ERG-overexpressing RWPE cells (a normal prostate cell line with low endogenous ERG) was found to validate that ERG recruited poly (ADP-ribose) polymerase 1 (PARP1) and protein kinase, DNA-activated, catalytic polypeptide (DNA-PKcs) into co-existing complexes at ERG-regulated loci[38]. Other experiments have verified that ETS upregulation in primary prostate epithelial cells induce DNA double strand breaks in terms of γ-H2AX foci. Interestingly, targeted inhibition of endogenous ERG decreased the elevated levels of γ-H2AX. It is noteworthy that pharmacological inhibition of PARP amplified the DNA damage response in ETS-positive cancer cells. Simultaneously, PARP inhibition was found to severely compromise ERG-mediated invasion and intravasation by abrogation of ERG-mediated mRNA induction of progression-associated genes such as EZH2[38].

The vitamin D metabolism also reportedly modulates the role of TMPRSS2-ERG in prostate tumorigenesis. For example, some indications have emerged that prostate tumors with high levels of vitamin D (1,25-dihydroxyvitamin D3) receptors (VDR) are twice as likely to be TMPRSS2-ERG fusion-positive than those with the low VDR levels[39]. Cells treated with VDR agonist EB1089 demonstrated genesis of TMPRSS2-ERG in both AR-negative as well as in AR-positive cells[40].

Using hTERT/shp53/CDK4 to immortalize the primary prostate epithelial (EP) cells reportedly forms tumors in an in vivo model[41]. In contrast, AR-transfected (EP-AR) cells formed distinct nodules in the prostate. In addition, TMPRSS2-ERG-transfected EP-AR cells formed large malignant tumors. Interleukin 1 receptor, type II (IL1R2) and serine peptidase inhibitor, Kunitz type 1 (SPINT1) are upstream regulators of zinc finger E-box binding homeobox 2 (ZEB2) expression thus respectively upregulating and repressing ZEB2. ChIP assay revealed TMPRSS2-ERG bound promoters of IL1R2, SPINT1 and ZEB1 genes, all of which were found to contain possible TMPRSS2-ERG binding sites. Overall, TMPRSS2-ERG directly binds and trans-activates ZEB1 while SPINT1 and IL1R2 respectively trans-activate and trans-repress to indirectly trigger ZEB2 expression[41].

Overexpression of an oncogenic ETS protein is involved in the majority of prostate tumorgenesis[42]. Genome-wide binding analysis has progressively enhanced our understanding of over-expressing ETS proteins by chromosomal rearrangement. RAS/ERK target genes were reported to bind to ETS/AP-1 sequences and become activated by oncogenic ETS proteins without activation of the RAS/ERK pathway[43]. Accordingly, upregulation of oncogenic ETS proteins can substitute for the RAS/ERK pathway activation in prostate cells[42]. This finding is important because fusion-positive prostate cancer cells can express the target genes of the RAS/ERK signaling pathway and thus resist treatment options.

Prostate-specific membrane antigen (PSMA) is upregulated in the adenocarcinoma of prostate cancer. TMPRSS2-ERG positive cells have a different gene network as treatment of VCaP cells with androgen analog resulted in the suppression of PSMA[44]. It was reported that ERG overexpression and nuclear translocation can activate Wnt signaling. However, treatment of prostate cancer cells with the analogue of 3,3'-diindolylmethane (BR-DIM) and curcumin inhibited AR/TMPRSS2-ERG/Wnt signaling[45]. In addition, ERG-positive prostate cancers are strongly histone deacetylase 1 (HDAC1)-positive and there is an over-expression of wingless-type MMTV integration site family (WNT)-associated pathways and the simultaneous suppression of tumor necrosis factors and cell death pathways[46]. Moreover, ERG overexpression increased the frizzled family receptor 4 (FZD4) expressions whereas ERG null cells declined in FZD4 at both the mRNA and protein levels. Laboratory investigations indicated that spatial-temporal behavior of the Wnt signaling pathway was disrupted in fusion-positive prostate cancer cells. This was verified using the T-cell factor/lymphoid enhancer factor (TCF/LEF) GFP Reporter Assay in GFP-ERG-transfected RWPE1 cells. The results clearly presented a 2.4-fold increase in WNT signaling in response to ERG overexpression and, contrarily, activity of the WNT pathway was decreased 3-fold by the targeted inhibition of ERG[47].

This section has focused on fusion-positive prostate cancer cells, which have misrepresented signaling cascades. We have described current research of the cell-type-specific genome-wide binding patterns of ERG and regulating mechanisms by TMPRSS2-ERG encoded fusion products in prostate cancer cells. Signaling components of linear pathways were identified, including membrane receptors and transcription factors, in an exploration of its molecular mechanisms. In general, various signaling pathways are dysregulated in TMPRSS2-ERG fusion-positive prostate cancer cells.

Direct binding of ERG can be validated by several methods, such as in vitro binding assays[48], promoter assays, and ChIP/polymerase chain reaction[49]. Other approaches such as ChIP with promoter array analysis (ChIP-chip)[50] and ChIP followed by sequencing (ChIP-seq)[49] also provide robust analyses for the genome-wide mapping of protein-binding patterns. In addition, using promoter-tiling arrays provides a remarkably improved chromatin-binding landscape of downstream effectors of multiple signal transduction cascades which may help to co-ordinate the prostate tumorigenesis. Genome-wide analyses are very important in cancer research and allow for the clarification and stratification of the detailed mechanisms for progression in prostate cancer.

Recent work showed ubiquitin ligase, such as ring finger and WD repeat domain 2, E3 ubiquitin protein ligase (RFWD2; COP1), functions as the tumor suppressor and also downregulates the ets variant 1 (ETV1), ETV4 and ETV5. However, it is worth noting that the truncated ETV1 encoded by TMPRSS2:ETV1 loses the major RFWD2 binding ability and becomes more stable than its wild-type counterpart. Animal model studies further verified that RFWD2 deficiency upregulated ETV1 level and enhanced uncontrolled cellular growth and early stage of prostate malignancy[51].

Overexpressed genes in fusion-positive prostate cancer cells

Recent research in prostate cancer biology has further clarified that ERG is up-regulated in the glands of the peripheral zone as compared to the transitional zone[52]. Analysis of the deregulated genes indicated that fusion-negative prostate tumor tissues were more similar to normal controls, while fusion-positive prostate tumor tissues displayed distinct deregulation of transcription.

Convergence of information suggests that different genes are tightly inter-connected with the occurrence of fusion transcripts in prostate cancer. We call attention to the biological and clinical features of oncogenic ERG and the therapeutic strategies in targeting the ERG network. For example, cysteine-rich secretory protein 3 (CRISP3) gene expression was found to be associated with the ERG condition, since it was overexpressed in TMPRSS2-ERG fusion-positive prostate tumors as compared to normal tissue. Laboratory findings indicated that CRISP3 is a direct target of ERG and is strongly overexpressed in prostate cancers with the TMPRSS2-ERG fusion gene[53]. Consistently, the pim-1 oncogene (PIM1) is a serine/threonine kinase which is frequently upregulated in prostate cancer. Chip assays demonstrated that TMPRSS2-ERG was found to be directly attached to the PIM1 promoter. Overexpression of PIM1 induced by TMPRSS2-ERG upregulation considerably modified cyclin B1 levels and the targeted inhibition of TMPRSS2-ERG suppressed PIM1 induction[54]. ERG target genes such as calcium channel, voltage-dependent, L type, α-1D subunit (CACNA1D) were significantly upregulated in TMPRSS2-ERG positive prostate cancer cells[39]. Osteopontin (OPN) is an extracellular matrix glycophosphoprotein involved in the metastasis. Using in vitro and in vivo molecular assays, it was reported that ERG stimulates OPN expression through targeting ETS binding sites in the OPN promoter. Transient transfection of TMPRSS2-ERG in prostate cancer cells stimulated endogenous OPN expression[55].

ETS RNA interference strategies were used to confirm that ETS affected the levels of seven tumor-associated ERG target genes, including phospholipase A1 member A (PLA1A), calcium channel, voltage-dependent, L type, alpha 1D subunit (CACNA1D), ATPase, aminophospholipid transporter, class I, type 8A, member 2 (ATP8A2), major histocompatibility complex, class II, DM beta (HLA-DMB), phosphodiesterase 3B, cGMP-inhibited (PDE3B), tudor domain containing 1 (TDRD1), and transmembrane BAX inhibitor motif containing 1 (TMBIM1) and two tumor-associated ETV1 target genes (FK506 binding protein 10, 65 kDa (FKBP10) and glycine-N-acyltransferase-like 2 (GLYATL2)[56].

TMPRSS2-ERG encoded fusion products were reported to induce the expression of TLR4[57]. Using BPH-1 and RWPE-1-fERG cells, ERG level was found to be associated with the overexpression of integrin-linked kinase (ILK) and its downstream effectors zinc-finger transcription factor Snail and lymphoid enhancer-binding factor 1 (LEF1). Targeted inhibition of ERG may downregulate the ILK, Snail and LEF1 gene expressions[58]. Mechanistic targeting of rapamycin (serine/threonine kinase) (mTOR) signaling is also activated in fusion-positive prostate cancer cells. Loss of pSer-2448 mTOR resulted in the full activation of Mtor[59]. c-myc is overexpressed in TMPRSS2-ERG fusion-positive prostate cancer cells as compared to normal tissue[60]. However, c-myc is also overexpressed in fusion negative tumors as compared to normal tissue[20]. Therefore, the relationship between c-myc and TMPRSS2-ERG fusion is still warranted to further investigate. Furthermore, fusion-positive prostate cancer cells were reported to downregulate frizzled receptors, overexpress the Rho GDP-dissociation inhibitor (RhoGDIB)[61], and overexpress the SRY (sex determining region Y)-box 9 (SOX9) gene[62].

Cellular studies suggest that recruitment of ERG promotes local H3K4 methylation and the subsequent binding of forkhead box A1 (FOXA1). FOXA1 is essential for androgen-stimulated binding of AR to the target genes[62]. Furthermore, ERG enhances the expression of various genes by controlling the methylation status of the promoter region of the target genes. For example, Tudor domain-containing protein 1 (TDRD1) was found to differentially regulate between fusion-positive and fusion-negative prostate cancer cells. The promoter of TDRD1 is hypomethylated and TDRD1 becomes overexpressed in ERG overexpressing prostate cancer cells[63]. It has lately been shown that phosphorylated ERG regulated expression of chemokine (C-X-C motif) receptor 4 (CXCR4) in prostate cancer cells. The I kappa B (IKK) and AKT kinases were noted to phosphorylate ERG at Serine 81 and 215, respectively[64], which were identified by their inhibitors such as BMS34551 and AKT Inhibitor IV.

The migratory and invasive potential of prostate cancer cells was noted to be regulated by ERG mediated expression of Metalloproteinase 9 and Plexin A2[65]. Increasingly it is being realized that ligand independent activation of AR is regulated in CACNA1D overexpressing prostate cancer cells. Mechanistically it was reported that ERG induced expression of CACNA1D promoted entry of calcium ions into cytosol[66].

The above explains how TMPRSS2-ERG encoded fusion products impair cell cycle checkpoints and promote proliferation. It appears that fusion-positive prostate cancer cells have a well-orchestrated network of coactivators and co-repressors, and that dysregulated signaling cascades also crosstalk and contribute in carcinogenesis. Next we address the quantity control of AR, ERG and the regulatory machinery of AR signaling.

miRNA mediated regulation of the androgen receptor and its associated protein network

It is well known that overexpression of AR contributes to antiandrogen resistance by amplifying signal output, and by changing the regular response to antagonists[67]. However, it is also important to mention that the loss of AR regulating miRNA signatures is a central aspect that underlies AR overexpression. In following section we discuss AR regulation by subsets of miRNA and their expression patterns in cancer cells.

It has reported that androgen-induced AR binds to the miR-21 promoter, signifying direct transcriptional regulation and considerable prostate carcinogenesis. However, inhibition of miR-21 decreased uncontrolled cellular proliferation[68].

A recent study has indicated that various miRNAs act as tumor suppressors and transiently transfecting cells with miR-331-3p reduced phosphorylated v-akt murine thymoma viral oncogene homolog 1 (AKT1) content[69]. Animal model studies verified that crossing TMPRSS2-ERG mice with prostate-specific AKT transgenic mice generated bigenic mice that developed more florid lesions. It is therefore now well acclaimed that TMPRSS2-ERG fusion alone is not enough to induce prostate intraepithelial neoplasia (PIN) but co-existence/co-occurrence of heterozygous Pten deletion in fusion positive cells dramatically promotes PIN[70].

In addition the v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian) (ERBB2) is another important receptor that is dysregulated in prostate cancer[69]. Contradictory findings have been presented regarding the role of this receptor in prostate cancer. It was reported that overexpression of ERBB2 activated AR pathway in prostate cancer cells in an androgen-deficient milieu[71]. However, ERBB-2 reportedly decreases the expression of endogenous AR and androgen-regulated PSA in LNCaP cells[72]. Truncated androgen receptors in prostate cancer 22Rv1 cells can bind DNA in the absence of ligand and repress the ERBB2 gene repression and for the 22Rv1 cell castration resistant phenotype[73]. Notably, targeted inhibition of ERBB2 effectively degraded AR and reduced its Ser(81) phosphorylation in prostate cancer cells[74]. Another research group has indicated that ERBB2/ERBB3 can maintain AR protein levels and ERBB2/ERBB3 were found to be attached to the promoter/enhancer of androgen-regulated genes in hormone-refractory prostate cancer[75]. ERBB2 and ERBB3 considerably increase the androgen-dependent AR transactivation of reporter genes in prostate cancer cells[76]. Targeted inhibition of ERBB2 kinase severely impaired androgen receptor recruitment to the androgen responsive enhancer in LNCaP cells[77].

Given that miR-331-3p represses ERBB2 expression and signal transduction in prostate cancer cells it seems reasonable to note that ERBB2 targeting destabilizes AR. However negative regulation of ERBB2 by miRNA is antagonized by the U-rich element located near the distal miR-331-3p target site in the ERBB2 3'-untranslated region (UTR). A detailed mechanistic investigation indicated that specific binding of the RNA binding protein- ELAV (embryonic lethal, abnormal vision, Drosophila)-like 1 (Hu antigen R) (HuR; ELAVL1) to this U-rich element momentously enhanced ERBB2 expression in prostate cancer cells[69, 78]. The 3-UTR of AR mRNA contains UC-rich consensus regions such as 5'-C(U)(n)C motif and a 3'-CCCUCCC poly(C)-binding protein motif. Analysis of the UC-rich region indicated the presence of a specific binding motif for ELAVL1[79]. Enforced expression of the miR-34a precursor into paclitaxel resistant prostate cancer cells resulted in decreases in ELAVL1[80]. Xenografting miR-34a competent prostate cancer cells in nude mice notably repressed tumor growth as miR-34a suppressed the assembly and function of the c-Myc-Skp2-Miz1 complex[81]. Therefore, it is understandable that miRNA mediated control of AR is lost in TMPRSS2-ERG positive prostate cancer and ELAVL1 stabilizes the expression of AR and ERBB2 which synchronously trigger the expression of cancer promoting genes.

Interestingly, over-expression of constitutively active AKT results in a proliferative advantage. Contrary to the proliferation enhancing potential of AKT, over-expression of ERG promoted cellular migration. ERG triggered the migratory potential of cancer cells by the overexpression of CXCR4 and ADAM metallopeptidase with a thrombospondin type 1 motif, 1 (ADAMTS1) as ChIP assay demonstrated direct binding of ERG to the promoter region for both CXCR4 and ADAMTS1[82]. In the CXCR4 promoter, several consensus sequences of ERG binding sites were identified and it was noted that an androgen agonist (R1881) can induce the mRNA expressions of both ERG and CXCR4 genes in TMPRSS2-ERG fusion-positive VCaP cells. Conversely, targeted inhibition of ERG by siRNA can inhibit the gene expressions of ERG and CXCR4 and prevents the upregulation of the androgen-induced CXCR4 expression in VCaP cells[83]. However, it is also relevant to mention that CXCR4 is negatively regulated by miR-139. Use of antagomirs against miR-139 rescued the CXCR4 expression. Gastric cancer cells were reported to use a specific mechanism to repress the expression of miR-139 via the interaction of ERBB2 with CD44[84]. A conflicting report suggests that no relationship exists between CXCR4 mRNA overexpression and TMPRSS2-ERG[85].

Notably, androgen and AR can transcriptionally and post-transcriptionally regulate the MiR-23a27a24-2 cluster in prostate cancer cells[86]. For example, in response to androgen, AR was reported to associate with the miR-23a27a24-2 promoter, initiate its transient transcription, and enhance androgen-induced processing from primiR-23a27a24-2 to its mature form premiR-23a27a24-2. In particular, miR-27a can negatively regulate a corepressor of AR, namely prohibitin, and has therapeutic potential for prostate cancer.

Furthermore, miR 488[87] and miR-let-7c[88] reportedly downregulate the transcriptional activity of AR. miR-133 can negatively regulate the epidermal growth factor receptor (EGFR)[89]. miR-130a, miR-203 and miR-205 work synchronously to target components involved in mitogen activated kinase-like protein (MAPK) and AR signaling pathways[90]. It is noteworthy that isoflavone demethylates the methylation status in the promoter of miR-29a and miR-1256, resulting in an overexpression of miR-29a and miR-1256, which can directly target the tripartite motif containing 68 (TRIM68)[91]. TRIM68 interacts with AR and enhances transcriptional activity of the AR target genes[92].

A recent report suggests that AR and the heterogeneous nuclear ribonucleoprotein K (HNRNPK) colocalize in the nucleoplasm and both were synchronously regulated by bicalutamide and/or 4-hydroxy-tamoxifen (BIC/4OHT) treatment[93]. Functional HNRNPK binding sites were reported to locate in 5'-UTR of AR mRNA. Further analysis revealed that HNRNPK can inhibit translation of the truncated AR without 5'-UTR, as additional HNRNPK binding sites were located at the AR open reading frame and its 3'-UTR[94]. HNRNPK and VEGF-A are direct targets of miR-205 and miR-29b, respectively[95]. Similarly, CD44 and v-akt murine thymoma viral oncogene homolog 2 (AKT2) are direct targets of miR-708[96].

Next we discuss the tissue-specific miRNA control of PTEN in several cancer cells. Previous reports have shown that different miRNA subsets modulate PTEN, thus restoring the cancer promoting functionality of AKT. Various tissue-specific studies show PTEN was negatively regulated by several miRNAs, e.g., miR-21, miR-221 and miR-222 in gastric cancer[97, 98]; miR-93 in ovarian cancer[99]; miR-519d in liver cancer[100]; miR-214 in non-small cell lung cancer[101]; and miR-153[102] and miR-21[103] in prostate cancer.

We currently lack a complete understanding of the mechanisms which promote loss of PTEN in fusion-positive prostate cancer cells, and an improved understanding of PTEN targeted miRNA-network would be of immense interest. Intriguingly, a recent study indicated that prostate cancer cells treated with resveratrol displayed down regulated miR-17-92, miRs-106a and miRs-106b oncogenic clusters, thus upregulating PTEN[104].

Quantitative control of ERG in prostate cancer cells

Evidence exists that ERG interferes AR signaling by inhibiting AR expression via recruiting H3K27 methyltransferase, a Polycomb group protein named as enhancer of zeste homolog 2 (Drosophila) (EZH2)[29]. Increasingly it is being recognized that targeted inhibition of ERG in the hormone-starved VCaP cells significantly repressed the expression of EZH2 and increased the expression of AR protein[29]. EZH2 is negatively regulated by miR-101 as genomic loss of miR-101 in the cancer leads to the upregulation of EZH2[105]. EZH2 is also targeted by the let-7 family of microRNAs and prostate cancer cells pretreated with BR-DIM displayed an up-regulated let-7 family and down-regulated EZH2 expression[106]. Furthermore, there is significant proof that miR-196a and miR-196b negatively regulate ERG[107]. Fitting together the scattered pieces of this jigsaw puzzle indicates that the disturbance of miRNA mediated regulation of ERG and EZH2 in prostate cancer requires detailed investigation.

TMPRSS2-ERG encoded protein targeting

The treatment of prostate cancer is being revolutionized by an improved comprehension of the genetic events that occur in the progression of the disease. These TMPRSS2-ERG encoded fusion products and DNA interactions have been investigated that explore the contribution of these proteins to oncogenesis and therapeutic resistance.

It has been convincingly demonstrated that heterocyclic diamidine specifically targets part of the ERG DNA recognition site[48]. It is encouraging to note an increased interest in inducing apoptosis in fusion-positive prostate cancer cells and disulfiram/sunitinib cotreatment induced apoptosis in TMPRSS2-ERG fusion-positive VCaP prostate cancer cells[108]. RNA interference strategies are also being used to target the T/E fusion junction in vivo with specific siRNAs delivered via liposomal nanovectors, a promising therapy for prostate cancer[109]. Using cDNA arrays, several gene transcripts that potentially cause TMPRSS2-ERG gene fusion were identified as being effectively downregulated by curcumin. Furthermore, curcumin reportedly inhibited expressions of EGFR and ERBB2 receptors in prostate cancer cell lines[110]. High throughput technologies have provided potential compounds which are effective in inhibiting ERG and ETV1 mediated transcription in a reporter assay. Using this approach, it was reported that the inhibitor of the EWS-FLI1 oncoprotein in Ewing’s Sarcoma (YK-4-279) can downregulate the gene expressions of ERG and ETV1 downstream target genes in ETV1 or ERG fusion-positive prostate cancer cells. More interestingly, ERG inhibition by siRNA was unresponsive to YK-4-279 in VCaP cells[111]. The traditional Chinese herbal medicine cryptotanshinone (CTS) was reported to be an AR inhibitor, suppressing androgen/AR-mediated cell proliferation and PSA expression through a remarkably effective inhibition of AR dimerization. CTS efficiently suppress the cell growth of castration resistant cells and the DHT-induced AR target genes (PSA, TMPRSS2, and TMEPA1) in the VCaP-luciferase xenograft mouse model[112].

ERG binds and inhibits histone acetyltransferases, resulting in the abrogation of p53 mediated expression of p21 and Bax. However, HDAC is active in fusion-positive prostate cancer cells. Intriguingly, experiments in ERG-positive VCaP cells treated with HDAC inhibitors, e.g., valproic acid and trichostatin-A, can induce apoptosis, enhance p53 acetylation, induce p21/Waf1/CIP1, and inhibit TMPRSS2-ERG expression[113].

Similarly, HDAC inhibitors were reported to inhibit the ERG-fusion gene expression, whereas the trichostatin-A significantly inhibits the ERG-associated gene signature. Synergistic administration of HDAC inhibitors (Trichostatin A, MS-275 and suberoylanilide hydroxamic acid) and AR antagonists (flutamide) result in the cytoplasmic retention of AR, indicating inhibition of androgen signaling[114]. Exposing ERG overexpressing and PTEN-deficient prostate cancer cells to a combined treatment of PARP inhibitor (rucaparib) and radiation induced senescence. In contrast, PTEN competent cells were treated to verify whether a PTEN deficiency induced senescence, with results indicating that PTEN sufficient DU145 cells showed almost no senescence. Moreover, rucaparib combined with a low dose radiation may induce persistent DNA damage in terms of γH2AX foci and considerably reduced cell survival[115]. Celastrol is a well-known NF-kB inhibitor and oncogenic fusion protein. Expressing prostate cancer cells pretreated with celastrol was reported to dose-dependently inhibit TMPRSS2-ERG fusion, AR and AR3 gene expression[116]. There is a direct evidence suggesting that a deubiquitinase namely ubiquitin-specific peptidase 9, X-linked (USP9X) can regulate the ERG protein expression in prostate cancer VCaP cells. For example, USP9X inhibitor (WP1130) downregulated ERG levels and inhibited cell proliferation and migration in prostate tumors. WP1130 also considerably abrogated tumor angiogenesis in ERG-overexpressing VcaP cells xenograft nude mice[117].

On the TRAIL of TMPRSS2-ERG encoded fusion products targeting

New experimental and preclinical data suggests that the tumor necrosis factor (ligand) superfamily, member 10 (TNFSF10; TRAIL) binds to several distinct receptors. Structural studies have shown that DR4 and DR5 contain the intracellular death domain (DD) which is required for apoptosis following receptor ligation. Cancer cells also display decoy receptor 1 (DcR1) and DcR2 and these are unable to cause apoptosis due to a complete or partial deletion of the intracellular DD, respectively[118–120]. Despite considerable work to overcome TRAIL resistance in prostate cancer cells, we still have no insight into the mechanics of TRAIL mediated signaling in fusion-positive prostate cancer cells. Recently, low levels of androgen are reported to be potent inducers of apoptosis in prostate cancer cells. DR5 was noted to be dramatically enhanced in cancer cells treated with low levels of androgen. On the contrary, pretreatment with high concentration of androgen induced pro-survival signals in TRAIL treated prostate cancer cells[121].

Contemporary studies suggested that HDAC inhibitor (Trichostatin A) converted the phenotype of human prostatic cancer cell line DU145 from resistant to sensitive. Treatment with Trichostatin A can activate caspase-9 and release mitochondrial cytochrome c and diablo, IAP-binding mitochondrial protein (DIABLO; Smac) in TRAIL resistant prostate cancer cells[122]. Similarly, HDAC inhibitors (depsipeptide and MS-275) were reported to effectively enhance TRAIL gene therapy of LNCaP prostate cancer cells[123]. Suberolylanilide hydroxamic acid and TRAIL synergistically induced apoptosis in LNCaP cells[124].

Conclusion

Genomic rearrangement has added another layer of complexity to prostate cancer investigation and has been emerged as major challenge to targeted therapeutic research. Our understanding of the mechanisms which act as triggers to genomic rearrangements is incomplete. We still need to determine which signaling cascades are misrepresented and contribute to genomic rearrangements, and which tumor suppressor signaling pathways are inactivated in fusion positive prostate cancer cells. Furthermore, our understanding of the impairment of apoptosis in TMPRSS2-ERG positive cancer cells is also incomplete. Fuller understanding of the mechanisms which inhibit pro-apoptotic proteins and promote anti-apoptotic proteins would provide a significant gain towards the development of personalized medicine. TRAIL mediated signaling in rearranged prostate cancer cells has not been adequately investigated, and a deeper understanding of the death and decoy receptors in fusion positive prostate cancer cells is essential to testing of synthetic and natural compounds to restore TRAIL mediated signaling in prostate cancer cells. Similarly, fewer studies have investigated the targeting of different signaling pathways in fusion positive prostate cancer cells. Other important questions include how DNA damage signaling regulates genomic rearrangements in prostate cancer cells and how this DNA damage repair signaling can be targeted to suppress genomic instability. Research is also required to determine how DNA damage inducing chemotherapeutic drugs contribute to the genesis of genomic rearrangements in prostate cancer cells. Recent improvements have been made in the visualization and quantification of the components of TMPRSS2-ERG signaling network[125], thus providing a better picture of different signaling pathways in TMPRSS2-ERG positive prostate cancer cells.

Functional interdependencies were explored between the molecular components in fusion-positive prostate cancer cells. The less appreciated facet of identification of dysregulated protein network needs extensive research to characterize the proteome of fusion-positive prostate cancer cells. This approach can be used to systematically explore the molecular complexity and relationships of fusion-positive prostate cancer cells. Furthermore, advances in classification of many cancer promoting genes and miRNA signatures for uncovering the biological mechanism of oncogenic TMPRSS2-ERG fusions associated genomic changes have been summarized, along with the drug targets and biomarkers for prostate cancer development.

References

  1. Ribarska T, Bastian KM, Koch A, Schulz WA: Specific changes in the expression of imprinted genes in prostate cancer–implications for cancer progression and epigenetic regulation. Asian J Androl. 2012, 14 (3): 436-450.

    PubMed Central  PubMed  CAS  Google Scholar 

  2. Kumar-Sinha C, Tomlins SA, Chinnaiyan AM: Recurrent gene fusions in prostate cancer. Nat Rev Cancer. 2008, 8 (7): 497-511.

    PubMed Central  PubMed  CAS  Google Scholar 

  3. Chiu YT, Liu J, Tang K, Wong YC, Khanna KK, Ling MT: Inactivation of ATM/ATR DNA damage checkpoint promotes androgen induced chromosomal instability in prostate epithelial cells. PLoS One. 2012, 7 (12): e51108-

    PubMed Central  PubMed  CAS  Google Scholar 

  4. Bonaccorsi L, Nesi G, Nuti F, Paglierani M, Krausz C, Masieri L, Serni S, Proietti-Pannunzi L, Fang Y, Jhanwar SC, Orlando C, Carini M, Forti G, Baldi E, Luzzatto L: Persistence of expression of the TMPRSS2:ERG fusion gene after pre-surgery androgen ablation may be associated with early prostate specific antigen relapse of prostate cancer: preliminary results. J Endocrinol Invest. 2009, 32 (7): 590-596.

    PubMed  CAS  Google Scholar 

  5. Lin C, Yang L, Tanasa B, Hutt K, Ju BG, Ohgi K, Zhang J, Rose DW, Fu XD, Glass CK, Rosenfeld MG: Nuclear receptor-induced chromosomal proximity and DNA breaks underlie specific translocations in cancer. Cell. 2009, 139 (6): 1069-1083.

    PubMed Central  PubMed  CAS  Google Scholar 

  6. Haffner MC, Aryee MJ, Toubaji A, Esopi DM, Albadine R, Gurel B, Isaacs WB, Bova GS, Liu W, Xu J, Meeker AK, Netto G, De Marzo AM, Nelson WG, Yegnasubramanian S: Androgen-induced TOP2B-mediated double-strand breaks and prostate cancer gene rearrangements. Nat Genet. 2010, 42 (8): 668-675.

    PubMed Central  PubMed  CAS  Google Scholar 

  7. Rubin MA: ETS rearrangements in prostate cancer. Asian J Androl. 2012, 14 (3): 393-399.

    PubMed Central  PubMed  CAS  Google Scholar 

  8. Albano F, Anelli L, Zagaria A, Coccaro N, Casieri P, Rossi AR, Vicari L, Liso V, Rocchi M, Specchia G: Non random distribution of genomic features in breakpoint regions involved in chronic myeloid leukemia cases with variant t(9;22) or additional chromosomal rearrangements. Mol Cancer. 2010, 9: 120-

    PubMed Central  PubMed  Google Scholar 

  9. Han S, Brenner JC, Sabolch A, Jackson W, Speers C, Wilder-Romans K, Knudsen KE, Lawrence TS, Chinnaiyan AM, Feng FY: Targeted radiosensitization of ETS fusion-positive prostate cancer through PARP1 inhibition. Neoplasia. 2013, 15 (10): 1207-1217.

    PubMed Central  PubMed  Google Scholar 

  10. Narod SA, Seth A, Nam R: Fusion in the ETS gene family and prostate cancer. Br J Cancer. 2008, 99 (6): 847-851.

    PubMed Central  PubMed  CAS  Google Scholar 

  11. Shah RB, Chinnaiyan AM: The discovery of common recurrent transmembrane protease serine 2 (TMPRSS2)-erythroblastosis virus E26 transforming sequence (ETS) gene fusions in prostate cancer: significance and clinical implications. Adv Anat Pathol. 2009, 16 (3): 145-153.

    PubMed  CAS  Google Scholar 

  12. Clark JP, Cooper CS: ETS gene fusions in prostate cancer. Nat Rev Urol. 2009, 6 (8): 429-439.

    PubMed  CAS  Google Scholar 

  13. FitzGerald LM, Agalliu I, Johnson K, Miller MA, Kwon EM, Hurtado-Coll A, Fazli L, Rajput AB, Gleave ME, Cox ME, Ostrander EA, Stanford JL, Huntsman DG: Association of TMPRSS2-ERG gene fusion with clinical characteristics and outcomes: results from a population-based study of prostate cancer. BMC Cancer. 2008, 8: 230-

    PubMed Central  PubMed  Google Scholar 

  14. Turner NC, Reis-Filho JS: Genetic heterogeneity and cancer drug resistance. Lancet Oncol. 2012, 13 (4): e178-185.

    PubMed  Google Scholar 

  15. Lee AJ, Swanton C: Tumour heterogeneity and drug resistance: personalising cancer medicine through functional genomics. Biochem Pharmacol. 2012, 83 (8): 1013-1020.

    PubMed  CAS  Google Scholar 

  16. Gerlinger M, Swanton C: How Darwinian models inform therapeutic failure initiated by clonal heterogeneity in cancer medicine. Br J Cancer. 2010, 103 (8): 1139-1143.

    PubMed Central  PubMed  CAS  Google Scholar 

  17. Marusyk A, Almendro V, Polyak K: Intra-tumour heterogeneity: a looking glass for cancer?. Nat Rev Cancer. 2012, 12 (5): 323-334.

    PubMed  CAS  Google Scholar 

  18. Brabletz T: To differentiate or not–routes towards metastasis. Nat Rev Cancer. 2012, 12 (6): 425-436.

    PubMed  CAS  Google Scholar 

  19. Clark J, Merson S, Jhavar S, Flohr P, Edwards S, Foster CS, Eeles R, Martin FL, Phillips DH, Crundwell M, Christmas T, Thompson A, Fisher C, Kovacs G, Cooper CS: Diversity of TMPRSS2-ERG fusion transcripts in the human prostate. Oncogene. 2007, 26 (18): 2667-2673.

    PubMed  CAS  Google Scholar 

  20. Borno ST, Fischer A, Kerick M, Falth M, Laible M, Brase JC, Kuner R, Dahl A, Grimm C, Sayanjali B, Isau M, Rohr C, Wunderlich A, Timmermann B, Claus R, Plass C, Graefen M, Simon R, Demichelis F, Rubin MA, Sauter G, Schlomm T, Sultmann H, Lehrach H, Schweiger MR: Genome-wide DNA methylation events in TMPRSS2-ERG fusion-negative prostate cancers implicate an EZH2-dependent mechanism with miR-26a hypermethylation. Cancer Discov. 2012, 2 (11): 1024-1035.

    PubMed  Google Scholar 

  21. Grupp K, Diebel F, Sirma H, Simon R, Breitmeyer K, Steurer S, Hube-Magg C, Prien K, Pham T, Weigand P, Michl U, Heinzer H, Kluth M, Minner S, Tsourlakis MC, Izbicki JR, Sauter G, Schlomm T, Wilczak W: SPINK1 expression is tightly linked to 6q15- and 5q21-deleted ERG-fusion negative prostate cancers but unrelated to PSA recurrence. Prostate. 2013, 73 (15): 1690-1698.

    PubMed  CAS  Google Scholar 

  22. Sirma H, Broemel M, Stumm L, Tsourlakis T, Steurer S, Tennstedt P, Salomon G, Michl U, Haese A, Simon R, Sauter G, Schlomm T, Minner S: Loss of CDKN1B/p27Kip1 expression is associated with ERG fusion-negative prostate cancer, but is unrelated to patient prognosis. Oncol Lett. 2013, 6 (5): 1245-1252.

    PubMed Central  PubMed  CAS  Google Scholar 

  23. Stumm L, Burkhardt L, Steurer S, Simon R, Adam M, Becker A, Sauter G, Minner S, Schlomm T, Sirma H, Michl U: Strong expression of the neuronal transcription factor FOXP2 is linked to an increased risk of early PSA recurrence in ERG fusion-negative cancers. J Clin Pathol. 2013, 66 (7): 563-568.

    PubMed  CAS  Google Scholar 

  24. Grupp K, Boumesli R, Tsourlakis MC, Koop C, Wilczak W, Adam M, Sauter G, Simon R, Izbicki JR, Graefen M, Huland H, Steurer S, Schlomm T, Minner S, Quaas A: Int J Cancer. 2014

    Google Scholar 

  25. Fodde R, Smits R, Clevers H: APC, signal transduction and genetic instability in colorectal cancer. Nat Rev Cancer. 2001, 1 (1): 55-67.

    PubMed  CAS  Google Scholar 

  26. Schwartzman J, Mongoue-Tchokote S, Gibbs A, Gao L, Corless CL, Jin J, Zarour L, Higano C, True LD, Vessella RL, Wilmot B, Bottomly D, McWeeney SK, Bova GS, Partin AW, Mori M, Alumkal J: A DNA methylation microarray-based study identifies ERG as a gene commonly methylated in prostate cancer. Epigenetics. 2011, 6 (10): 1248-1256.

    PubMed Central  PubMed  CAS  Google Scholar 

  27. Mani RS, Iyer MK, Cao Q, Brenner JC, Wang L, Ghosh A, Cao X, Lonigro RJ, Tomlins SA, Varambally S, Chinnaiyan AM: TMPRSS2-ERG-mediated feed-forward regulation of wild-type ERG in human prostate cancers. Cancer Res. 2011, 71 (16): 5387-5392.

    PubMed Central  PubMed  CAS  Google Scholar 

  28. Hoogland AM, Jenster G, van Weerden WM, Trapman J, van der Kwast T, Roobol MJ, Schroder FH, Wildhagen MF, van Leenders GJ: ERG immunohistochemistry is not predictive for PSA recurrence, local recurrence or overall survival after radical prostatectomy for prostate cancer. Mod Pathol. 2012, 25 (3): 471-479.

    PubMed  CAS  Google Scholar 

  29. Yu J, Yu J, Mani RS, Cao Q, Brenner CJ, Cao X, Wang X, Wu L, Li J, Hu M, Gong Y, Cheng H, Laxman B, Vellaichamy A, Shankar S, Li Y, Dhanasekaran SM, Morey R, Barrette T, Lonigro RJ, Tomlins SA, Varambally S, Qin ZS, Chinnaiyan AM: An integrated network of androgen receptor, polycomb, and TMPRSS2-ERG gene fusions in prostate cancer progression. Cancer Cell. 2010, 17 (5): 443-454.

    PubMed Central  PubMed  CAS  Google Scholar 

  30. Bastus NC, Boyd LK, Mao X, Stankiewicz E, Kudahetti SC, Oliver RT, Berney DM, Lu YJ: Androgen-induced TMPRSS2:ERG fusion in nonmalignant prostate epithelial cells. Cancer Res. 2010, 70 (23): 9544-9548.

    PubMed Central  PubMed  Google Scholar 

  31. Hermans KG, van Marion R, van Dekken H, Jenster G, van Weerden WM, Trapman J: TMPRSS2:ERG fusion by translocation or interstitial deletion is highly relevant in androgen-dependent prostate cancer, but is bypassed in late-stage androgen receptor-negative prostate cancer. Cancer Res. 2006, 66 (22): 10658-10663.

    PubMed  CAS  Google Scholar 

  32. Lehmusvaara S, Erkkila T, Urbanucci A, Waltering K, Seppala J, Larjo A, Tuominen VJ, Isola J, Kujala P, Lahdesmaki H, Kaipia A, Tammela T, Visakorpi T: Chemical castration and anti-androgens induce differential gene expression in prostate cancer. J Pathol. 2012, 227 (3): 336-345.

    PubMed  CAS  Google Scholar 

  33. Ateeq B, Vellaichamy A, Tomlins SA, Wang R, Cao Q, Lonigro RJ, Pienta KJ, Varambally S: Role of dutasteride in pre-clinical ETS fusion-positive prostate cancer models. Prostate. 2012, 72 (14): 1542-1549.

    PubMed  CAS  Google Scholar 

  34. Brase JC, Johannes M, Mannsperger H, Falth M, Metzger J, Kacprzyk LA, Andrasiuk T, Gade S, Meister M, Sirma H, Sauter G, Simon R, Schlomm T, Beissbarth T, Korf U, Kuner R, Sultmann H: TMPRSS2-ERG -specific transcriptional modulation is associated with prostate cancer biomarkers and TGF-beta signaling. BMC Cancer. 2011, 11: 507-

    PubMed Central  PubMed  CAS  Google Scholar 

  35. Taylor BS, Schultz N, Hieronymus H, Gopalan A, Xiao Y, Carver BS, Arora VK, Kaushik P, Cerami E, Reva B, Antipin Y, Mitsiades N, Landers T, Dolgalev I, Major JE, Wilson M, Socci ND, Lash AE, Heguy A, Eastham JA, Scher HI, Reuter VE, Scardino PT, Sander C, Sawyers CL, Gerald WL: Integrative genomic profiling of human prostate cancer. Cancer Cell. 2010, 18 (1): 11-22.

    PubMed Central  PubMed  CAS  Google Scholar 

  36. Mao X, Boyd LK, Yanez-Munoz RJ, Chaplin T, Xue L, Lin D, Shan L, Berney DM, Young BD, Lu YJ: Chromosome rearrangement associated inactivation of tumour suppressor genes in prostate cancer. Am J Cancer Res. 2011, 1 (5): 604-617.

    PubMed Central  PubMed  Google Scholar 

  37. Ummanni R, Barreto F, Venz S, Scharf C, Barett C, Mannsperger HA, Brase JC, Kuner R, Schlomm T, Sauter G, Sultmann H, Korf U, Bokemeyer C, Walther R, Brummendorf TH, Balabanov S: Peroxiredoxins 3 and 4 are overexpressed in prostate cancer tissue and affect the proliferation of prostate cancer cells in vitro. J Proteome Res. 2012, 11 (4): 2452-2466.

    PubMed  CAS  Google Scholar 

  38. Brenner JC, Ateeq B, Li Y, Yocum AK, Cao Q, Asangani IA, Patel S, Wang X, Liang H, Yu J, Palanisamy N, Siddiqui J, Yan W, Cao X, Mehra R, Sabolch A, Basrur V, Lonigro RJ, Yang J, Tomlins SA, Maher CA, Elenitoba-Johnson KS, Hussain M, Navone NM, Pienta KJ, Varambally S, Feng FY, Chinnaiyan AM: Mechanistic rationale for inhibition of poly(ADP-ribose) polymerase in ETS gene fusion-positive prostate cancer. Cancer Cell. 2011, 19 (5): 664-678.

    PubMed Central  PubMed  CAS  Google Scholar 

  39. Hendrickson WK, Flavin R, Kasperzyk JL, Fiorentino M, Fang F, Lis R, Fiore C, Penney KL, Ma J, Kantoff PW, Stampfer MJ, Loda M, Mucci LA, Giovannucci E: Vitamin D receptor protein expression in tumor tissue and prostate cancer progression. J Clin Oncol. 2011, 29 (17): 2378-2385.

    PubMed Central  PubMed  CAS  Google Scholar 

  40. Washington MN, Weigel NL: 1{alpha},25-Dihydroxyvitamin D3 inhibits growth of VCaP prostate cancer cells despite inducing the growth-promoting TMPRSS2:ERG gene fusion. Endocrinology. 2010, 151 (4): 1409-1417.

    PubMed Central  PubMed  CAS  Google Scholar 

  41. Leshem O, Madar S, Kogan-Sakin I, Kamer I, Goldstein I, Brosh R, Cohen Y, Jacob-Hirsch J, Ehrlich M, Ben-Sasson S, Goldfinger N, Loewenthal R, Gazit E, Rotter V, Berger R: TMPRSS2/ERG promotes epithelial to mesenchymal transition through the ZEB1/ZEB2 axis in a prostate cancer model. PLoS One. 2011, 6 (7): e21650-

    PubMed Central  PubMed  CAS  Google Scholar 

  42. Hollenhorst PC, Ferris MW, Hull MA, Chae H, Kim S, Graves BJ: Oncogenic ETS proteins mimic activated RAS/MAPK signaling in prostate cells. Genes Dev. 2011, 25 (20): 2147-2157.

    PubMed Central  PubMed  CAS  Google Scholar 

  43. Hollenhorst PC: RAS/ERK pathway transcriptional regulation through ETS/AP-1 binding sites. Small GTPases. 2012, 3 (3): 154-158.

    PubMed Central  PubMed  Google Scholar 

  44. Yin L, Rao P, Elson P, Wang J, Ittmann M, Heston WD: Role of TMPRSS2-ERG gene fusion in negative regulation of PSMA expression. PLoS One. 2011, 6 (6): e21319-

    PubMed Central  PubMed  CAS  Google Scholar 

  45. Li Y, Kong D, Wang Z, Ahmad A, Bao B, Padhye S, Sarkar FH: Inactivation of AR/TMPRSS2-ERG/Wnt signaling networks attenuates the aggressive behavior of prostate cancer cells. Cancer Prev Res (Phila). 2011, 4 (9): 1495-1506.

    CAS  Google Scholar 

  46. Iljin K, Wolf M, Edgren H, Gupta S, Kilpinen S, Skotheim RI, Peltola M, Smit F, Verhaegh G, Schalken J, Nees M, Kallioniemi O: TMPRSS2 fusions with oncogenic ETS factors in prostate cancer involve unbalanced genomic rearrangements and are associated with HDAC1 and epigenetic reprogramming. Cancer Res. 2006, 66 (21): 10242-10246.

    PubMed  CAS  Google Scholar 

  47. Gupta S, Iljin K, Sara H, Mpindi JP, Mirtti T, Vainio P, Rantala J, Alanen K, Nees M, Kallioniemi O: FZD4 as a mediator of ERG oncogene-induced WNT signaling and epithelial-to-mesenchymal transition in human prostate cancer cells. Cancer Res. 2010, 70 (17): 6735-6745.

    PubMed  CAS  Google Scholar 

  48. Nhili R, Peixoto P, Depauw S, Flajollet S, Dezitter X, Munde MM, Ismail MA, Kumar A, Farahat AA, Stephens CE, Duterque-Coquillaud M, David Wilson W, Boykin DW, David-Cordonnier MH: Targeting the DNA-binding activity of the human ERG transcription factor using new heterocyclic dithiophene diamidines. Nucleic Acids Res. 2013, 41 (1): 125-138.

    PubMed Central  PubMed  CAS  Google Scholar 

  49. Rickman DS, Chen YB, Banerjee S, Pan Y, Yu J, Vuong T, Perner S, Lafargue CJ, Mertz KD, Setlur SR, Sircar K, Chinnaiyan AM, Bismar TA, Rubin MA, Demichelis F: ERG cooperates with androgen receptor in regulating trefoil factor 3 in prostate cancer disease progression. Neoplasia. 2010, 12 (12): 1031-1040.

    PubMed Central  PubMed  CAS  Google Scholar 

  50. Kubosaki A, Tomaru Y, Tagami M, Arner E, Miura H, Suzuki T, Suzuki M, Suzuki H, Hayashizaki Y: Genome-wide investigation of in vivo EGR-1 binding sites in monocytic differentiation. Genome Biol. 2009, 10 (4): R41-

    PubMed Central  PubMed  Google Scholar 

  51. Vitari AC, Leong KG, Newton K, Yee C, O'Rourke K, Liu J, Phu L, Vij R, Ferrando R, Couto SS, Mohan S, Pandita A, Hongo JA, Arnott D, Wertz IE, Gao WQ, French DM, Dixit VM: COP1 is a tumour suppressor that causes degradation of ETS transcription factors. Nature. 2011, 474 (7351): 403-406.

    PubMed  CAS  Google Scholar 

  52. Shaikhibrahim Z, Lindstrot A, Ellinger J, Rogenhofer S, Buettner R, Perner S, Wernert N: The peripheral zone of the prostate is more prone to tumor development than the transitional zone: is the ETS family the key?. Mol Med Rep. 2012, 5 (2): 313-316.

    PubMed  CAS  Google Scholar 

  53. Ribeiro FR, Paulo P, Costa VL, Barros-Silva JD, Ramalho-Carvalho J, Jeronimo C, Henrique R, Lind GE, Skotheim RI, Lothe RA, Teixeira MR: Cysteine-rich secretory protein-3 (CRISP3) is strongly up-regulated in prostate carcinomas with the TMPRSS2-ERG fusion gene. PLoS One. 2011, 6 (7): e22317-

    PubMed Central  PubMed  CAS  Google Scholar 

  54. Magistroni V, Mologni L, Sanselicio S, Reid JF, Redaelli S, Piazza R, Viltadi M, Bovo G, Strada G, Grasso M, Gariboldi M, Gambacorti-Passerini C: ERG deregulation induces PIM1 over-expression and aneuploidy in prostate epithelial cells. PLoS One. 2011, 6 (11): e28162-

    PubMed Central  PubMed  CAS  Google Scholar 

  55. Flajollet S, Tian TV, Flourens A, Tomavo N, Villers A, Bonnelye E, Aubert S, Leroy X, Duterque-Coquillaud M: Abnormal expression of the ERG transcription factor in prostate cancer cells activates osteopontin. Mol Cancer Res. 2011, 9 (7): 914-924.

    PubMed  CAS  Google Scholar 

  56. Paulo P, Ribeiro FR, Santos J, Mesquita D, Almeida M, Barros-Silva JD, Itkonen H, Henrique R, Jeronimo C, Sveen A, Mills IG, Skotheim RI, Lothe RA, Teixeira MR: Molecular subtyping of primary prostate cancer reveals specific and shared target genes of different ETS rearrangements. Neoplasia. 2012, 14 (7): 600-611.

    PubMed Central  PubMed  CAS  Google Scholar 

  57. Wang J, Cai Y, Shao LJ, Siddiqui J, Palanisamy N, Li R, Ren C, Ayala G, Ittmann M: Activation of NF-{kappa}B by TMPRSS2/ERG fusion isoforms through toll-like receptor-4. Cancer Res. 2011, 71 (4): 1325-1333.

    PubMed Central  PubMed  CAS  Google Scholar 

  58. Becker-Santos DD, Guo Y, Ghaffari M, Vickers ED, Lehman M, Altamirano-Dimas M, Oloumi A, Furukawa J, Sharma M, Wang Y, Dedhar S, Cox ME: Integrin-linked kinase as a target for ERG-mediated invasive properties in prostate cancer models. Carcinogenesis. 2012, 33 (12): 2558-2567.

    PubMed Central  PubMed  CAS  Google Scholar 

  59. Muller J, Ehlers A, Burkhardt L, Sirma H, Steuber T, Graefen M, Sauter G, Minner S, Simon R, Schlomm T, Michl U: Loss of pSer2448-mTOR expression is linked to adverse prognosis and tumor progression in ERG-fusion-positive cancers. Int J Cancer. 2013, 132 (6): 1333-1340.

    PubMed  Google Scholar 

  60. Hawksworth D, Ravindranath L, Chen Y, Furusato B, Sesterhenn IA, McLeod DG, Srivastava S, Petrovics G: Overexpression of C-MYC oncogene in prostate cancer predicts biochemical recurrence. Prostate Cancer Prostatic Dis. 2010, 13 (4): 311-315.

    PubMed  CAS  Google Scholar 

  61. Chow A, Amemiya Y, Sugar L, Nam R, Seth A: Whole-transcriptome analysis reveals established and novel associations with TMPRSS2:ERG fusion in prostate cancer. Anticancer Res. 2012, 32 (9): 3629-3641.

    PubMed  CAS  Google Scholar 

  62. Cai C, Wang H, He HH, Chen S, He L, Ma F, Mucci L, Wang Q, Fiore C, Sowalsky AG, Loda M, Liu XS, Brown M, Balk SP, Yuan X: ERG induces androgen receptor-mediated regulation of SOX9 in prostate cancer. J Clin Invest. 2013, 123 (3): 1109-1122.

    PubMed Central  PubMed  CAS  Google Scholar 

  63. Kacprzyk LA, Laible M, Andrasiuk T, Brase JC, Borno ST, Falth M, Kuner R, Lehrach H, Schweiger MR, Sultmann H: ERG induces epigenetic activation of Tudor domain-containing protein 1 (TDRD1) in ERG rearrangement-positive prostate cancer. PLoS One. 2013, 8 (3): e59976-

    PubMed Central  PubMed  CAS  Google Scholar 

  64. Chinni S, Singareddy R, Semaan L, Conley-Lacomb MK, St John J, Powell K, Iyer M, Smith D, Heilbrun LK, Shi D, Sakr W, Cher ML: Transcriptional regulation of CXCR4 in prostate tumor cells: Significance of TMPRSS2-ERG fusions. Mol Cancer Res. 2013, in press [PMID: 23918819]

    Google Scholar 

  65. Tian TV, Tomavo N, Huot L, Flourens A, Bonnelye E, Flajollet S, Hot D, Leroy X, de Launoit Y, Duterque-Coquillaud M: Identification of novel TMPRSS2:ERG mechanisms in prostate cancer metastasis: involvement of MMP9 and PLXNA2. Oncogene. 2013, in press [PMID: 23708657]

    Google Scholar 

  66. Chen R, Zeng X, Zhang R, Huang J, Kuang X, Yang J, Liu J, Tawfik O, Brantley Thrasher J, Li B: Ca1.3 channel alpha protein is overexpressed and modulates androgen receptor transactivation in prostate cancers. Urol Oncol. 2013, in press [PMID: 24054868]

    Google Scholar 

  67. Chen CD, Welsbie DS, Tran C, Baek SH, Chen R, Vessella R, Rosenfeld MG, Sawyers CL: Molecular determinants of resistance to antiandrogen therapy. Nat Med. 2004, 10 (1): 33-39.

    PubMed  Google Scholar 

  68. Ribas J, Ni X, Haffner M, Wentzel EA, Salmasi AH, Chowdhury WH, Kudrolli TA, Yegnasubramanian S, Luo J, Rodriguez R, Mendell JT, Lupold SE: miR-21: an androgen receptor-regulated microRNA that promotes hormone-dependent and hormone-independent prostate cancer growth. Cancer Res. 2009, 69 (18): 7165-7169.

    PubMed Central  PubMed  CAS  Google Scholar 

  69. Epis MR, Giles KM, Barker A, Kendrick TS, Leedman PJ: miR-331-3p regulates ERBB-2 expression and androgen receptor signaling in prostate cancer. J Biol Chem. 2009, 284 (37): 24696-24704.

    PubMed Central  PubMed  CAS  Google Scholar 

  70. Casey OM, Fang L, Hynes PG, Abou-Kheir WG, Martin PL, Tillman HS, Petrovics G, Awwad HO, Ward Y, Lake R, Zhang L, Kelly K: TMPRSS2- driven ERG expression in vivo increases self-renewal and maintains expression in a castration resistant subpopulation. PLoS One. 2012, 7 (7): e41668-

    PubMed Central  PubMed  CAS  Google Scholar 

  71. Berger R, Lin DI, Nieto M, Sicinska E, Garraway LA, Adams H, Signoretti S, Hahn WC, Loda M: Androgen-dependent regulation of Her-2/neu in prostate cancer cells. Cancer Res. 2006, 66 (11): 5723-5728.

    PubMed  CAS  Google Scholar 

  72. Cai C, Portnoy DC, Wang H, Jiang X, Chen S, Balk SP: Androgen receptor expression in prostate cancer cells is suppressed by activation of epidermal growth factor receptor and ErbB2. Cancer Res. 2009, 69 (12): 5202-5209.

    PubMed  CAS  Google Scholar 

  73. Pignon JC, Koopmansch B, Nolens G, Delacroix L, Waltregny D, Winkler R: Androgen receptor controls EGFR and ERBB2 gene expression at different levels in prostate cancer cell lines. Cancer Res. 2009, 69 (7): 2941-2949.

    PubMed  CAS  Google Scholar 

  74. Hsu FN, Yang MS, Lin E, Tseng CF, Lin H: The significance of Her2 on androgen receptor protein stability in the transition of androgen requirement in prostate cancer cells. Am J Physiol Endocrinol Metab. 2011, 300 (5): E902-908.

    PubMed  CAS  Google Scholar 

  75. Mellinghoff IK, Vivanco I, Kwon A, Tran C, Wongvipat J, Sawyers CL: HER2/neu kinase-dependent modulation of androgen receptor function through effects on DNA binding and stability. Cancer Cell. 2004, 6 (5): 517-527.

    PubMed  CAS  Google Scholar 

  76. Gregory CW, Whang YE, McCall W, Fei X, Liu Y, Ponguta LA, French FS, Wilson EM, Earp HS: Heregulin-induced activation of HER2 and HER3 increases androgen receptor transactivation and CWR-R1 human recurrent prostate cancer cell growth. Clin Cancer Res. 2005, 11 (5): 1704-1712.

    PubMed  CAS  Google Scholar 

  77. Liu Y, Majumder S, McCall W, Sartor CI, Mohler JL, Gregory CW, Earp HS, Whang YE: Inhibition of HER-2/neu kinase impairs androgen receptor recruitment to the androgen responsive enhancer. Cancer Res. 2005, 65 (8): 3404-3409.

    PubMed  CAS  Google Scholar 

  78. Epis MR, Barker A, Giles KM, Beveridge DJ, Leedman PJ: The RNA-binding protein HuR opposes the repression of ERBB-2 gene expression by microRNA miR-331-3p in prostate cancer cells. J Biol Chem. 2011, 286 (48): 41442-41454.

    PubMed Central  PubMed  CAS  Google Scholar 

  79. Yeap BB, Voon DC, Vivian JP, McCulloch RK, Thomson AM, Giles KM, Czyzyk-Krzeska MF, Furneaux H, Wilce MC, Wilce JA, Leedman PJ: Novel binding of HuR and poly(C)-binding protein to a conserved UC-rich motif within the 3'-untranslated region of the androgen receptor messenger RNA. J Biol Chem. 2002, 277 (30): 27183-27192.

    PubMed  CAS  Google Scholar 

  80. Kojima K, Fujita Y, Nozawa Y, Deguchi T, Ito M: MiR-34a attenuates paclitaxel-resistance of hormone-refractory prostate cancer PC3 cells through direct and indirect mechanisms. Prostate. 2010, 70 (14): 1501-1512.

    PubMed  CAS  Google Scholar 

  81. Yamamura S, Saini S, Majid S, Hirata H, Ueno K, Deng G, Dahiya R: MicroRNA-34a modulates c-Myc transcriptional complexes to suppress malignancy in human prostate cancer cells. PLoS One. 2012, 7 (1): e29722-

    PubMed Central  PubMed  CAS  Google Scholar 

  82. Carver BS, Tran J, Gopalan A, Chen Z, Shaikh S, Carracedo A, Alimonti A, Nardella C, Varmeh S, Scardino PT, Cordon-Cardo C, Gerald W, Pandolfi PP: Aberrant ERG expression cooperates with loss of PTEN to promote cancer progression in the prostate. Nat Genet. 2009, 41 (5): 619-624.

    PubMed Central  PubMed  CAS  Google Scholar 

  83. Cai J, Kandagatla P, Singareddy R, Kropinski A, Sheng S, Cher ML, Chinni SR: Androgens induce functional CXCR4 through ERG factor expression in TMPRSS2-ERG fusion-positive prostate cancer cells. Transl Oncol. 2010, 3 (3): 195-203.

    PubMed Central  PubMed  Google Scholar 

  84. Bao W, Fu HJ, Xie QS, Wang L, Zhang R, Guo ZY, Zhao J, Meng YL, Ren XL, Wang T, Li Q, Jin BQ, Yao LB, Wang RA, Fan DM, Chen SY, Jia LT, Yang AG: HER2 interacts with CD44 to up-regulate CXCR4 via epigenetic silencing of microRNA-139 in gastric cancer cells. Gastroenterology. 2011, 141 (6): 2076-2087. e2076

    PubMed  CAS  Google Scholar 

  85. de Muga S, Hernandez S, Salido M, Lorenzo M, Agell L, Juanpere N, Lorente JA, Serrano S, Lloreta J: CXCR4 mRNA overexpression in high grade prostate tumors: lack of association with TMPRSS2-ERG rearrangement. Cancer Biomark. 2012, 12 (1): 21-30.

    PubMed  CAS  Google Scholar 

  86. Fletcher CE, Dart DA, Sita-Lumsden A, Cheng H, Rennie PS, Bevan CL: Androgen-regulated processing of the oncomir miR-27a, which targets Prohibitin in prostate cancer. Hum Mol Genet. 2012, 21 (14): 3112-3127.

    PubMed  CAS  Google Scholar 

  87. Sikand K, Slaibi JE, Singh R, Slane SD, Shukla GC: miR 488* inhibits androgen receptor expression in prostate carcinoma cells. Int J Cancer. 2011, 129 (4): 810-819.

    PubMed  CAS  Google Scholar 

  88. Nadiminty N, Tummala R, Lou W, Zhu Y, Zhang J, Chen X, eVere White RW, Kung HJ, Evans CP, Gao AC: MicroRNA let-7c suppresses androgen receptor expression and activity via regulation of Myc expression in prostate cancer cells. J Biol Chem. 2012, 287 (2): 1527-1537.

    PubMed Central  PubMed  CAS  Google Scholar 

  89. Tao J, Wu D, Xu B, Qian W, Li P, Lu Q, Yin C, Zhang W: microRNA-133 inhibits cell proliferation, migration and invasion in prostate cancer cells by targeting the epidermal growth factor receptor. Oncol Rep. 2012, 27 (6): 1967-1975.

    PubMed  CAS  Google Scholar 

  90. Boll K, Reiche K, Kasack K, Morbt N, Kretzschmar AK, Tomm JM, Verhaegh G, Schalken J, von Bergen M, Horn F, Hackermuller J: MiR-130a, miR-203 and miR-205 jointly repress key oncogenic pathways and are downregulated in prostate carcinoma. Oncogene. 2013, 32 (3): 277-285.

    PubMed  CAS  Google Scholar 

  91. Li Y, Kong D, Ahmad A, Bao B, Dyson G, Sarkar FH: Epigenetic deregulation of miR-29a and miR-1256 by isoflavone contributes to the inhibition of prostate cancer cell growth and invasion. Epigenetics. 2012, 7 (8): 940-949.

    PubMed Central  PubMed  CAS  Google Scholar 

  92. Miyajima N, Maruyama S, Bohgaki M, Kano S, Shigemura M, Shinohara N, Nonomura K, Hatakeyama S: TRIM68 regulates ligand-dependent transcription of androgen receptor in prostate cancer cells. Cancer Res. 2008, 68 (9): 3486-3494.

    PubMed  CAS  Google Scholar 

  93. Barboro P, Repaci E, Ferrari N, Rubagotti A, Boccardo F, Balbi C: Androgen receptor and heterogeneous nuclear ribonucleoprotein K colocalize in the nucleoplasm and are modulated by bicalutamide and 4-hydroxy-tamoxifen in prostatic cancer cell lines. Prostate. 2011, 71 (13): 1466-1479.

    PubMed  CAS  Google Scholar 

  94. Mukhopadhyay NK, Kim J, Cinar B, Ramachandran A, Hager MH, Di Vizio D, Adam RM, Rubin MA, Raychaudhuri P, De Benedetti A, Freeman MR: Heterogeneous nuclear ribonucleoprotein K is a novel regulator of androgen receptor translation. Cancer Res. 2009, 69 (6): 2210-2218.

    PubMed Central  PubMed  CAS  Google Scholar 

  95. Szczyrba J, Nolte E, Hart M, Doll C, Wach S, Taubert H, Keck B, Kremmer E, Stohr R, Hartmann A, Wieland W, Wullich B, Grasser FA: Identification of ZNF217, hnRNP-K, VEGF-A and IPO7 as targets for microRNAs that are downregulated in prostate carcinoma. Int J Cancer. 2013, 132 (4): 775-784.

    PubMed  CAS  Google Scholar 

  96. Saini S, Majid S, Shahryari V, Arora S, Yamamura S, Chang I, Zaman MS, Deng G, Tanaka Y, Dahiya R: miRNA-708 control of CD44(+) prostate cancer-initiating cells. Cancer Res. 2012, 72 (14): 3618-3630.

    PubMed  CAS  Google Scholar 

  97. Zhang BG, Li JF, Yu BQ, Zhu ZG, Liu BY, Yan M: microRNA-21 promotes tumor proliferation and invasion in gastric cancer by targeting PTEN. Oncol Rep. 2012, 27 (4): 1019-1026.

    PubMed Central  PubMed  CAS  Google Scholar 

  98. Chun-Zhi Z, Lei H, An-Ling Z, Yan-Chao F, Xiao Y, Guang-Xiu W, Zhi-Fan J, Pei-Yu P, Qing-Yu Z, Chun-Sheng K: MicroRNA-221 and microRNA-222 regulate gastric carcinoma cell proliferation and radioresistance by targeting PTEN. BMC Cancer. 2010, 10: 367-

    PubMed Central  PubMed  Google Scholar 

  99. Fu X, Tian J, Zhang L, Chen Y, Hao Q: Involvement of microRNA-93, a new regulator of PTEN/Akt signaling pathway, in regulation of chemotherapeutic drug cisplatin chemosensitivity in ovarian cancer cells. FEBS Lett. 2012, 586 (9): 1279-1286.

    PubMed  CAS  Google Scholar 

  100. Fornari F, Milazzo M, Chieco P, Negrini M, Marasco E, Capranico G, Mantovani V, Marinello J, Sabbioni S, Callegari E, Cescon M, Ravaioli M, Croce CM, Bolondi L, Gramantieri L: In hepatocellular carcinoma miR-519d is up-regulated by p53 and DNA hypomethylation and targets CDKN1A/p21, PTEN, AKT3 and TIMP2. J Pathol. 2012, 227 (3): 275-285.

    PubMed  CAS  Google Scholar 

  101. Wang YS, Wang YH, Xia HP, Zhou SW, Schmid-Bindert G, Zhou CC: MicroRNA-214 regulates the acquired resistance to gefitinib via the PTEN/AKT pathway in EGFR-mutant cell lines. Asian Pac J Cancer Prev. 2012, 13 (1): 255-260.

    PubMed  Google Scholar 

  102. Wu Z, He B, He J, Mao X: Upregulation of miR-153 promotes cell proliferation via downregulation of the PTEN tumor suppressor gene in human prostate cancer. Prostate. 2013, 73 (6): 596-604.

    PubMed  CAS  Google Scholar 

  103. Liu LZ, Li C, Chen Q, Jing Y, Carpenter R, Jiang Y, Kung HF, Lai L, Jiang BH: MiR-21 induced angiogenesis through AKT and ERK activation and HIF-1alpha expression. PLoS One. 2011, 6 (4): e19139-

    PubMed Central  PubMed  CAS  Google Scholar 

  104. Dhar S, Hicks C, Levenson AS: Resveratrol and prostate cancer: promising role for microRNAs. Mol Nutr Food Res. 2011, 55 (8): 1219-1229.

    PubMed  CAS  Google Scholar 

  105. Varambally S, Cao Q, Mani RS, Shankar S, Wang X, Ateeq B, Laxman B, Cao X, Jing X, Ramnarayanan K, Brenner JC, Yu J, Kim JH, Han B, Tan P, Kumar-Sinha C, Lonigro RJ, Palanisamy N, Maher CA, Chinnaiyan AM: Genomic loss of microRNA-101 leads to overexpression of histone methyltransferase EZH2 in cancer. Science. 2008, 322 (5908): 1695-1699.

    PubMed Central  PubMed  CAS  Google Scholar 

  106. Kong D, Heath E, Chen W, Cher ML, Powell I, Heilbrun L, Li Y, Ali S, Sethi S, Hassan O, Hwang C, Gupta N, Chitale D, Sakr WA, Menon M, Sarkar FH: Loss of let-7 up-regulates EZH2 in prostate cancer consistent with the acquisition of cancer stem cell signatures that are attenuated by BR-DIM. PLoS One. 2012, 7 (3): e33729-

    PubMed Central  PubMed  CAS  Google Scholar 

  107. Coskun E, von der Heide EK, Schlee C, Kuhnl A, Gokbuget N, Hoelzer D, Hofmann WK, Thiel E, Baldus CD: The role of microRNA-196a and microRNA-196b as ERG regulators in acute myeloid leukemia and acute T-lymphoblastic leukemia. Leuk Res. 2011, 35 (2): 208-213.

    PubMed  CAS  Google Scholar 

  108. Ketola K, Kallioniemi O, Iljin K: Chemical biology drug sensitivity screen identifies sunitinib as synergistic agent with disulfiram in prostate cancer cells. PLoS One. 2012, 7 (12): e51470-

    PubMed Central  PubMed  CAS  Google Scholar 

  109. Shao L, Tekedereli I, Wang J, Yuca E, Tsang S, Sood A, Lopez-Berestein G, Ozpolat B, Ittmann M: Highly specific targeting of the TMPRSS2/ERG fusion gene using liposomal nanovectors. Clin Cancer Res. 2012, 18 (24): 6648-6657.

    PubMed Central  PubMed  CAS  Google Scholar 

  110. Thangapazham RL, Shaheduzzaman S, Kim KH, Passi N, Tadese A, Vahey M, Dobi A, Srivastava S, Maheshwari RK: Androgen responsive and refractory prostate cancer cells exhibit distinct curcumin regulated transcriptome. Cancer Biol Ther. 2008, 7 (9): 1427-1435.

    PubMed  CAS  Google Scholar 

  111. Rahim S, Beauchamp EM, Kong Y, Brown ML, Toretsky JA, Uren A: YK-4-279 inhibits ERG and ETV1 mediated prostate cancer cell invasion. PLoS One. 2011, 6 (4): e19343-

    PubMed Central  PubMed  CAS  Google Scholar 

  112. Xu D, Lin TH, Li S, Da J, Wen XQ, Ding J, Chang C, Yeh S: Cryptotanshinone suppresses androgen receptor-mediated growth in androgen dependent and castration resistant prostate cancer cells. Cancer Lett. 2012, 316 (1): 11-22.

    PubMed Central  PubMed  CAS  Google Scholar 

  113. Fortson WS, Kayarthodi S, Fujimura Y, Xu H, Matthews R, Grizzle WE, Rao VN, Bhat GK, Reddy ES: Histone deacetylase inhibitors, valproic acid and trichostatin-A induce apoptosis and affect acetylation status of p53 in ERG-positive prostate cancer cells. Int J Oncol. 2011, 39 (1): 111-119.

    PubMed Central  PubMed  CAS  Google Scholar 

  114. Bjorkman M, Iljin K, Halonen P, Sara H, Kaivanto E, Nees M, Kallioniemi OP: Defining the molecular action of HDAC inhibitors and synergism with androgen deprivation in ERG-positive prostate cancer. Int J Cancer. 2008, 123 (12): 2774-2781.

    PubMed  CAS  Google Scholar 

  115. Chatterjee P, Choudhary GS, Sharma A, Singh K, Heston WD, Ciezki J, Klein EA, Almasan A: PARP inhibition sensitizes to low dose-rate radiation TMPRSS2-ERG fusion gene-expressing and PTEN-deficient prostate cancer cells. PLoS One. 2013, 8 (4): e60408-

    PubMed Central  PubMed  CAS  Google Scholar 

  116. Shao L, Zhou Z, Cai Y, Castro P, Dakhov O, Shi P, Bai Y, Ji H, Shen W, Wang J: Celastrol suppresses tumor cell growth through targeting an AR-ERG-NF-kappaB pathway in TMPRSS2/ERG fusion gene expressing prostate cancer. PLoS One. 2013, 8 (3): e58391-

    PubMed Central  PubMed  CAS  Google Scholar 

  117. Wang S, Kollipara RK, Srivastava N, Li R, Ravindranathan P, Hernandez E, Freeman E, Humphries CG, Kapur P, Lotan Y, Fazli L, Gleave ME, Plymate SR, Raj GV, Hsieh JT, Kittler R: Ablation of the oncogenic transcription factor ERG by deubiquitinase inhibition in prostate cancer. Proc Natl Acad Sci U S A. 2014, in press [PMID: 24591637]

    Google Scholar 

  118. Farooqi AA, Rana A, Riaz AM, Khan A, Ali M, Javed S, Mukhtar S, Minhaj S, Rao JR, Rajpoot J, Amber R, Javed FA, Waqar Un N, Khanum R, Bhatti S: NutriTRAILomics in prostate cancer: time to have two strings to one's bow. Mol Biol Rep. 2012, 39 (4): 4909-4914.

    PubMed  CAS  Google Scholar 

  119. Farooqi AA, Butt G, Razzaq Z: Algae extracts and methyl jasmonate anti-cancer activities in prostate cancer: choreographers of 'the dance macabre'. Cancer Cell Int. 2012, 12 (1): 50-

    PubMed Central  PubMed  CAS  Google Scholar 

  120. Farooqi AA, Bhatti S, Ismail M: TRAIL and vitamins: opting for keys to castle of cancer proteome instead of open sesame. Cancer Cell Int. 2012, 12 (1): 22-

    PubMed Central  PubMed  CAS  Google Scholar 

  121. Wang D, Lu J, Tindall DJ: Androgens regulate TRAIL-induced cell death in prostate cancer cells via multiple mechanisms. Cancer Lett. 2013, 335 (1): 136-144.

    PubMed Central  PubMed  CAS  Google Scholar 

  122. Taghiyev AF, Guseva NV, Sturm MT, Rokhlin OW, Cohen MB: Trichostatin A (TSA) sensitizes the human prostatic cancer cell line DU145 to death receptor ligands treatment. Cancer Biol Ther. 2005, 4 (4): 382-390.

    PubMed  CAS  Google Scholar 

  123. Kasman L, Lu P, Voelkel-Johnson C: The histone deacetylase inhibitors depsipeptide and MS-275, enhance TRAIL gene therapy of LNCaP prostate cancer cells without adverse effects in normal prostate epithelial cells. Cancer Gene Ther. 2007, 14 (3): 327-334.

    PubMed  CAS  Google Scholar 

  124. Lakshmikanthan V, Kaddour-Djebbar I, Lewis RW, Kumar MV: SAHA-sensitized prostate cancer cells to TNFalpha-related apoptosis-inducing ligand (TRAIL): mechanisms leading to synergistic apoptosis. Int J Cancer. 2006, 119 (1): 221-228.

    PubMed  CAS  Google Scholar 

  125. Welch CM, Elliott H, Danuser G, Hahn KM: Imaging the coordination of multiple signalling activities in living cells. Nat Rev Mol Cell Biol. 2011, 12 (11): 749-756.

    PubMed Central  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This work was partly supported by the National Sun Yat-sen University-KMU Joint Research Project (#NSYSU-KMU 103-p014), the Ministry of Health and Welfare, Taiwan, Republic of China (MOHW103-TD-B-111-05), by Ministry of Economic Affairs, Taiwan, Republic of China (102-EC-17-A-01-05-0643, and 103-EC-17-A-01-04-0525).

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Ammad Ahmad Farooqi or Hsueh-Wei Chang.

Additional information

Competing interests

All authors declare that they have no competing interests.

Authors’ contributions

A-AF and H-WC integrated different points of searched literatures, and drafted the manuscript. M-FH, C-CC and C-LW conceived the idea, did literature search on specific points, and involved in discussion. All authors read and approved the final manuscript.

Rights and permissions

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Farooqi, A.A., Hou, MF., Chen, CC. et al. Androgen receptor and gene network: Micromechanics reassemble the signaling machinery of TMPRSS2-ERG positive prostate cancer cells. Cancer Cell Int 14, 34 (2014). https://doi.org/10.1186/1475-2867-14-34

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/1475-2867-14-34

Keywords