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Androgen Receptor and Gene Network: Micromechanics Reassemble The Farooqi et al. Cancer Cell International 2014, 14:34 http://www.cancerci.com/content/14/1/34 REVIEW Open Access Androgen receptor and gene network: Micromechanics reassemble the signaling machinery of TMPRSS2-ERG positive prostate cancer cells Ammad Ahmad Farooqi1*, Ming-Feng Hou2,3,4, Chien-Chi Chen5, Chun-Lin Wang5 and Hsueh-Wei Chang2,6,7,8* 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 cascades and targeting gene network in fusion positive pros- Multiple molecular signaling pathways overlap, integrate tate cancer cells. In addition, it also provides information and promote the progression of intraepithelial neoplasia about broadening landscape of over-expressed androgen and metastasis. Accumulating evidence has shown that receptor (AR) through loss of control of miRNA subsets. genomic rearrangements play a vital role in regulating differentiation, cell proliferation and invasive growth of prostate cancers [1]. Recently, the fusion genes from the Genomic instability ETS transcription factors like v-ets erythroblastosis virus Previous findings have linked aberrant genomic rearrange- E26 homolog (avian) (ERG) were identified and reportedly ments to tumor development. During tumorigenesis, upregulated in an androgen-dependent manner [2]. The malignant cells not only carry somatic mutations from the fusion gene-positive cells may transform their phenotypes founder cell but also contain other acquired mutations from indolent and local nodules to a more aggressive and from daughter cells. Moreover, DNA damage repair less differentiated type of prostate cancer cells [1]. This ignaling involved in androgen treated prostate cancer review mainly focuses on the representation of signaling cells. Androgen treatment can activate Ataxia telangiecta- sia mutated (ATM) and Ataxia telangiectasia and Rad3 * Correspondence: [email protected]; [email protected] related (ATR) in the immortalized normal prostate epithe- 1Laboratory for Translational Oncology and Personalized Medicine, Rashid lial HPr-1 AR cells. Moreover, knockdown of ATM and Latif Medical College, 35 Km Ferozepur Road, Lahore, Pakistan ATR in HPr-1 AR cells can induce transmembrane prote- 2Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan ase, serine 2 and ERG (TMPRSS2-ERG) fusion transcript Full list of author information is available at the end of the article [3]. Additionally, androgen ablation can downregulate the © 2014 Farooqi et al.; licensee 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. Farooqi et al. Cancer Cell International 2014, 14:34 Page 2 of 12 http://www.cancerci.com/content/14/1/34 expression of TMPRSS2:ERG [4]. AR facilitated recruit- fusion transcript were reported to 73% of primary prostate ment of activation-induced cytidine deaminase (AID) tumor samples and 43% samples taken from non-malignant and LINE-1 repeat-encoded ORF2 endonuclease for tissues [19]. Accordingly, the levels of TMPRSS2-ERG fu- TMPRSS2:ERG rearrangements [5]. Certain hints have sion transcript are correlated with the status of prostate emerged suggesting that androgen signaling induced cells in normal or malignancy. In addition, it is noted that co-recruitment of AR and TOP2B topoisomerase different established prostate cancer cell lines may have dif- (DNA) II beta 180 kDa (TOP2B) at genomic break- ferent statuses for TMPRSS2-ERG. For example, the hu- points of TMPRSS2-ERG, where TOP2B mediated man prostate cancer VCaP cells are TMPRSS2-ERG double stranded breaks and triggered this rearrangements positive with wild type AR, whereas human prostate cancer [6]. Mechanistically it was shown that AR bound to mul- LNCaP cells are TMPRSS2-ERG negative with mutated AR. tiple intronic regions near break sites in TMPRSS2 and The methylation may play an important role in regulat- ERG, suggesting that AR mediated juxtapositioning of ing the TMPRSS2-ERG fusion. For example, it was re- DNA breaks was essential for recombination and these ported that fusion negative tumors are heavily methylated genomic rearrangements appears to be nonrandom [7,8]. as compared to fusion positive samples in terms of meth- ERG-overexpressing cancer cells demonstrated higher ylated DNA immunoprecipitation sequencing [20]. The single-strand break repair (SSBR) rate and leaded to radi- enhancer of zeste homolog 2 (Drosophila) (EZH2), a his- ation resistance [9]. It is intriguing to note that knockdown tone methyltransferase, was upregulated in fusion negative of PARP1 poly (ADP-ribose) polymerase 1 (PARP1) in prostate tumor and controlled by miR-26a. Additionally, ERG-positive prostate cancer PC3 and DU145 cells may SPINK1 overexpression has a tight correlation with small resensitize radioresistant cancer cells. Targeted inhibition deletions of 6q15- and 5q21 in ERG negative prostate can- of a DNA SSBR protein (XRCC1) by siRNA in ERG- cers [21]. Loss of CDKN1B/p27Kip1 expression was ob- overexpressing cancer cells may impair ERG induced SSBR served in subset of ERG-negative, low-grade tumors [22]. and partially resensitize the cell radoresistance. In a xeno- In contrast, FOXP2 forkhead box P2 (FOXP2) and nibrin graft model, PARP1 inhibitor ABT-888 can recover the (NBN or NBS1) are overexpressed in fusion negative pros- ERG conferring radioresistance [9]. tate cancer cells [23,24]. Accordingly, These results suggested that the TMPRSS2: Prostate cancer and precursor lesions ERG fusion is nonrandom in genomic level but may be Moreover, it is becoming clear that high-grade prostatic random in cell type level. In the next section we will briefly intraepithelial neoplasia (HGPIN) is a precursor of some discuss difference of TMPRSS2-ERG positive and negative prostate carcinomas, and thus is often characterized by prostate cancer cells and how gene networks are regulated TMPRSS2-ERG fusion gene [10-12]. HGPIN is composed in fusion positive cancer cells. 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. Signal transduction cascades in fusion-positive prostate It is worth noting, prostates with carcinoma have more of cancer these hallmark foci than those without carcinoma. Pros- Prostate cancer is developed through a series of specific tate glands with extensive HGPIN have more multifocal genetic alterations. It requires initial clonal expansion, carcinomas at the same time. Development of HGPIN genomic instability, inactivation of tumor suppressor lesions occurs predominantly in the peripheral zone of the genes, overexpression of oncogenes, and disruption of prostate, which is believed to be the primary site of origin the spatial-temporal behavior of signaling cascades [25]. for most adenocarcinomas. This is in accordance with the With the landmark identification of a recurrent gene fact that HGPIN lesions may initially be polyclonal prolif- fusion event on chromosome 21 between the TMPRSS2 erations, with cells with TMPRSS2-ERG fusion being and ERG genes, prostate cancers are now categorized as diluted in a pool of cells which do not feature this alter- "fusion-positive" and "fusion-negative" [12]. Following ation. The HGPIN lesion may eventually be dominated by genomic rearrangement, the expression of transcription the clone with the TMPRSS2-ERG fusion as a result of factor ERG may be regulated through the promoter of clonal expansion, as evidenced by the analysis of ERG the androgen-responsive gene TMPRSS2. For example, overexpression in a subset of HGPIN lesions. TMPRSS2-ERG fusion products can bind to the ERG locus and result in an overexpression of wild-type ERG. TMPRSS2-ERG fusion in prostate normal and cancer
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