A pointed (PNT) domain characterizes the central part of ERG, which enables homo- and heterodimerization with other ETS factors [40,41]. Brenner J.C., Ateeq B., Li Y., Yocum A.K., Cao Q., Asangani I.A., Patel S., Wang X., Liang H., Yu J., et al. Shao J., Yan Y., Ding D., Wang D., He Y., Pan Y., Yan W., Kharbanda A., Li H., Huang H. Destruction of DNA-Binding Proteins by Programmable Oligonucleotide PROTAC (OPROTAC): Effective Targeting of LEF1 and ERG. Liu J., Chen H., Kaniskan H.., Xie L., Chen X., Jin J., Wei W. TF-PROTACs Enable Targeted Degradation of Transcription Factors. Wei G.-H., Badis G., Berger M.F., Kivioja T., Palin K., Enge M., Bonke M., Jolma A., Varjosalo M., Gehrke A.R., et al. Metzger E., Willmann D., McMillan J., Forne I., Metzger P., Gerhardt S., Petroll K., von Maessenhausen A., Urban S., Schott A.K., et al. TMPRSS2:ERG gene fusion associated with lethal prostate cancer in a watchful waiting cohort. Black men were less likely to get comprehensive genetic profiling of their tumors early in treatment, the study of nearly 13,000 men with advanced prostate cancer found. A recent in vitro study suggested that it might be worth re-assessing these results according to the PTEN, GSK3b phosphorylation and FBW7 status, since genotoxic therapies induce ERG degradation in prostate cancer cells only when these three proteins are functional [50]. Shaulian E., Karin M. AP-1 as a regulator of cell life and death. Singareddy R., Semaan L., Conley-LaComb M.K., St. John J., Powell K., Iyer M., Smith D., Heilbrun L.K., Shi D., Sakr W., et al. Oncogenic ETS proteins mimic activated RAS/MAPK signaling in prostate cells. Erkizan H.V., Kong Y., Merchant M., Schlottmann S., Barber-Rotenberg J.S., Yuan L., Abaan O.D., Chou T., Dakshanamurthy S., Brown M.L., et al. Brase J.C., Johannes M., Mannsperger H., Flth M., Metzger J., Kacprzyk L.A., Andrasiuk T., Gade S., Meister M., Sirma H., et al. Electrostatic repulsion causes anticooperative DNA binding between tumor suppressor ETS transcription factors and JUNFOS at composite DNA sites. Complex patterns of ETS gene alteration arise during cancer development in the human prostate. The presence of the T/E fusion . Thangapazham R., Saenz F., Katta S., Mohamed A.A., Tan S.H., Petrovics G., Srivastava S., Dobi A. Multiple TMPRSS2-ERG variants have been identified, some encoding the full-length ERG or a TMPRSS2-ERG fusion protein, while others produce an N-terminal truncated ERG, which retain the PNT and ETS domains that are essential for the transcription factor activity. In recent years, several small molecule inhibitors were developed to specifically inhibit ERG activity. Moreover, inhibition of the enzymatic activity of these proteins hampered ERG-mediated transcriptional regulation with a consequent reduction in the capacity of prostate cancer cells overexpressing ERG to invade [65]. Wang S., Kollipara R.K., Humphries C.G., Ma S.-H., Hutchinson R., Li R., Siddiqui J., Tomlins S.A., Raj G.V., Kittler R., et al. The upper right inset summarizes the inhibitors of ERG activity developed so far, which: (A) affect TMPRSS2-ERG mRNA stability (siRNA targeting the fusion breakpoint); (B) decrease ERG protein stability and inhibit DNA binding; (C) alter ERG interaction with cofactors and transcriptional activity or exacerbate DNA damage. Treatment of ERG overexpressing cells with the PARP inhibitor olaparib not only decreased ERG-mediated cell invasion and intravasation, but also inhibited growth in mouse xenograft models [65]. In a series of cancer cases assayed with comprehensive genomic profiling (CGP) in the course of clinical care, we reviewed the frequency of TMPRSS2-ERG fusions in patient tumors of various histologic subtypes. Rahim S., Beauchamp E.M., Kong Y., Brown M.L., Toretsky J.A., ren A. YK-4-279 Inhibits ERG and ETV1 Mediated Prostate Cancer Cell Invasion. Sizemore G.M., Pitarresi J.R., Balakrishnan S., Ostrowski M.C. ARV-110: An oral androgen receptor PROTAC degrader for prostate cancer. Molife L.R., Attard G., Fong P.C., Karavasilis V., Reid A.H.M., Patterson S., Riggs C.E., Higano C., Stadler W.M., McCulloch W., et al. At the molecular levels, SPOP is upregulated by ERG, dampens AR signaling and sustains ERG activity through degradation of the histone reader ZMYND11. A promising route to exploit cancer-specific vulnerabilities is represented by therapies tailored to patient genomic characteristics. Nicholas T.R., Strittmatter B.G., Hollenhorst P.C. For further investigations in precision treatment, the development of preclinical models representing the complex prostate tumor heterogeneity are mandatory. The bromodomain protein BRD4 was also shown to facilitate DNA repair by promoting NHEJ and the expression of DNA repair genes, favoring TMPRSS2 and ERG gene fusion [85]. Recurrent Fusion of TMPRSS2 and ETS Transcription Factor Genes in Prostate Cancer. However, genomic alterations in other DNA damage response (DDR) genes have not been consistently predictive of clinical response to PARP inhibition. Baca S.C., Prandi D., Lawrence M.S., Mosquera J.M., Romanel A., Drier Y., Park K., Kitabayashi N., MacDonald T.Y., Ghandi M., et al. TMPRSS2 - ERG is a high-frequency fusion gene expressed in prostate cancer and plays a vital role in carcinogenesis. The transcription factor Erg is essential for definitive hematopoiesis and the function of adult hematopoietic stem cells. The https:// ensures that you are connecting to the Although ERG knockout or expression inhibition via Cas9 and nuclease-null deactivated Cas9 (dCas9) functionalized with effector domains [187,188,189,190,191,192] might be difficult to exploit in the context of ERG rearrangements given their position mostly in non-coding regions and their long distance from the promoter, other strategies might be pursued. Among the ETS members, ERG (ETS-related gene) plays important roles in normal physiology and tumorigenesis, with its overexpression detected in several tumor types, including Ewings sarcoma, hematological malignancies and prostate cancer (PCa). First-in-human phase I study of ARV-110, an androgen receptor (AR) PROTAC degrader in patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC) following enzalutamide (ENZ) and/or abiraterone (ABI). Cerveira N., Ribeiro F.R., Peixoto A., Costa V., Henrique R., Jernimo C., Teixeira M.R. Crosstalk between ERG activity and the NOTCH and NF-B pathways was reported in PCa. TMPRSS2-ERG fusion co-opts master transcription factors and activates NOTCH signaling in primary prostate cancer. Hong Z., Zhang W., Ding D., Huang Z., Yan Y., Cao W., Pan Y., Hou X., Weroha S.J., Karnes R.J., et al. Received 2022 Jan 26; Accepted 2022 Feb 16. The small molecule YK-4-279 was originally identified by surface plasmon resonance (SPR) and developed for Ewings sarcoma to block EWS-FLI1 binding to DHX9/RNA helicase A (RHA), an important cofactor for its oncogenic activity [145]. EMAGE mouse embryo spatial gene expression database: 2010 update. Identification of a Small Molecule That Selectively Inhibits ERG-Positive Cancer Cell Growth. Yuan L., Le Bras A., Sacharidou A., Itagaki K., Zhan Y., Kondo M., Carman C.V., Davis G.E., Aird W.C., Oettgen P. ETS-related Gene (ERG) Controls Endothelial Cell Permeability via Transcriptional Regulation of the Claudin 5 (CLDN5) Gene. Federal government websites often end in .gov or .mil. prostate cancer genes. Accordingly, rearrangements and/or aberrant expression of ERG are found in acute myeloid leukemia [33,34,35]. ERG dependence distinguishes developmental control of hematopoietic stem cell maintenance from hematopoietic specification. Finally, a role in preventing differentiation into hypertrophic cells was also observed for ERG in articular chondrocytes [36,37]. Clark J., Merson S., Jhavar S., Flohr P., Edwards S., Foster C.S., Eeles R., Martin F.L., Phillips D.H., Crundwell M., et al. We discuss the strategies developed in recent years to inhibit ERG activity, the current therapeutic utility of ERG fusion detection in PCa patients, and the possible future approaches to target ERG fusion-positive tumors. Experimental Design: We generated a Pten -negative/ Trp53 -mutated/ ERG -overexpressing mouse model of prostate cancer and integrated RNA-sequencing with ERG chromatin immunoprecipitation-sequencing (ChIP-seq) to identify pathways regulated by ERG in the context of Pten / Trp53 alteration. Here, we summarize the attempts made over the past years to repress ERG activity, the current use of ERG fusion detection and the strategies that might be utilized in the future to treat ERG fusion-positive tumors. Prostate epithelial genes define therapy-relevant prostate cancer molecular subtype. ERG binds to DNA at specific sequences and is targeted by several post-translational modifications (Ac = acetylation, dark green; Me = methylation, orange; Ub = ubiquitination, blue; and Pi = phosphorylation; light green) controlled by diverse proteins (dark green, orange, blue and light green boxes). Winters B., Brown L., Coleman I., Nguyen H., Minas T.Z., Kollath L., Vasioukhin V., Nelson P., Corey E., ren A., et al. Understanding the Role of ETS-Mediated Gene Regulation in Complex Biological Processes. Loss of FOXO1 Cooperates with TMPRSS2ERG Overexpression to Promote Prostate Tumorigenesis and Cell Invasion. combined ENCODE ChIP-seq data with drug-induced expression profiles to pinpoint small molecules perturbing transcription factor activity. Accordingly, we aimed to establish a resource of patient-derived xenograft (PDX) models that . A Computational Drug Repositioning Approach for Targeting Oncogenic Transcription Factors. Discovery of ARD-69 as a Highly Potent Proteolysis Targeting Chimera (PROTAC) Degrader of Androgen Receptor (AR) for the Treatment of Prostate Cancer. ERG (ETS-related gene) is a member of the E-26 transformation-specific (ETS) family of transcription factors. Abou-Ouf H., Zhao L., Bismar T.A. To bypass this problem, DNA oligonucleotide can be linked to an E3 ligase ligand. The TMPRSS2/ERG (T/E) fusion gene is present in approximately 50% of prostate cancers and promotes tumor progression in vivo. Yuan L., Nikolova-Krstevski V., Zhan Y., Kondo M., Bhasin M., Varghese L., Yano K., Carman C.V., Aird W.C., Oettgen P. Antiinflammatory Effects of the ETS Factor ERG in Endothelial Cells Are Mediated Through Transcriptional Repression of the Interleukin-8 Gene. Function of phosphorylation of NF-kB p65 ser536 in prostate cancer oncogenesis. King J.C., Xu J., Wongvipat J., Hieronymus H., Carver B.S., Leung D.H., Taylor B.S., Sander C., Cardiff R.D., Couto S.S., et al. Although only useful in half of all PCa patients, the non-invasive detection of TMPRSS2-ERG fusion might reduce patient overtreatment. Associations of Luminal and Basal Subtyping of Prostate Cancer with Prognosis and Response to Androgen Deprivation Therapy. Therefore, inhibiting ERG might represent an important step to improve treatment efficacy for patients with ERG-positive prostate tumors. Robinson D., van Allen E.M., Wu Y.-M., Schultz N., Lonigro R.J., Mosquera J.M., Montgomery B., Taplin M.-E., Pritchard C.C., Attard G., et al. Their expression and activity are deregulated in many tumor types, with some members having a tumor-suppressive role, while others promote and sustain oncogenic behaviors [6]. Alternative approaches to inhibit ERG activity included the use of RNA interference technology and peptides. An Integrated Network of Androgen Receptor, Polycomb, and TMPRSS2-ERG Gene Fusions in Prostate Cancer Progression. Importantly, inhibition of ERG activity in prostate cancer cells decreases their viability. This work was funded by the European Research Council (ERC) under the European Unions Horizon 2020 research and innovation program (grant agreement No 648670) to F.D., Fondazione AIRC (IG 19221) to F.D. Scand. Among the ETS factors are both transcriptional activators and repressors, which control a plethora of processes, including differentiation, proliferation, apoptosis, tissue remodeling and angiogenesis [5]. These preliminary results are compelling, yet the system might suffer from low specificity due to the fact that the binding motif of ERG can be recognized and bound also by other ETS members. Introduction of the ERG gene fusion product into primary or immortalized benign prostate epithelial cells induced an invasion-associated transcriptional program but did . It controls the expression of endothelial cell-specific genes (e.g., VE-cadherin, claudin5, vWF, endoglin, eNOS) and regulates the WNT/b-catenin pathway, promoting vascular stability and growth [20,26,27]. Patients with high-grade PIN and positive for ERG overexpression showed a higher frequency of PCa progression compared to ERG-negative patients [154]. This interaction is not dependent on DNA and JUN/FOS have minimal effects on the DNA binding affinity of ERG to ERG-AP-1 composite sites [55]. the contents by NLM or the National Institutes of Health. Genomic correlates of clinical outcome in advanced prostate cancer. Moreover, the depletion of ERG in murine embryonic stem cells decreases their capacity to differentiate into endothelial cells [21]. Genomic hallmarks of localized, non-indolent prostate cancer. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (, ERG, prostate cancer, transcription factor, therapeutic strategies, {"type":"clinical-trial","attrs":{"text":"NCT02657005","term_id":"NCT02657005"}}. Biology of EWS/ETS fusions in Ewings family tumors. National Library of Medicine ERG signaling in prostate cancer is driven through PRMT5-dependent methylation of the androgen receptor. Bradley D., Rathkopf D., Dunn R., Stadler W.M., Liu G., Smith D.C., Pili R., Zwiebel J., Scher H., Hussain M. Vorinostat in advanced prostate cancer patients progressing on prior chemotherapy (National Cancer Institute Trial 6862): Trial results and interleukin-6 analysis: A study by the Department of Defense Prostate Cancer Clinical Trial Consortium and Universi. Antibody-Based Detection of ERG Rearrangement-Positive Prostate Cancer. AP-1 transcription factors are dimers of basic region-leucine zipper (bZIP) proteins belonging to the JUN, FOS, MAF and ATF sub-families and play important roles in cellular proliferation, survival, locomotion and tumor biology [54]. Careers, Unable to load your collection due to an error. Schapira M., Calabrese M.F., Bullock A.N., Crews C.M. TMPRSS2 and ERG are about 3Mbp apart in the same orientation on chromosome 21. Eigl B.J., North S., Winquist E., Finch D., Wood L., Sridhar S.S., Powers J., Good J., Sharma M., Squire J.A., et al. Expression of TMPRSS2: ERG gene fusion in prostate cancer cells is an important prognostic factor for cancer progression. Sun C., Dobi A., Mohamed A., Li H., Thangapazham R.L., Furusato B., Shaheduzzaman S., Tan S.-H., Vaidyanathan G., Whitman E., et al. YK-4-279 treatment inhibited ERG and ETV1 transcriptional activity and consequent cell invasion in VCaP and LNCaP cells, respectively, but had no effect on PC-3 cells overexpressing ETV4 [146]. Mani R.-S., Tomlins S.A., Callahan K., Ghosh A., Nyati M.K., Varambally S., Palanisamy N., Chinnaiyan A.M. The ubiquitin ligase TRIM25 targets ERG for degradation in prostate cancer. Teply B.A., Wang H., Luber B., Sullivan R., Rifkind I., Bruns A., Spitz A., DeCarli M., Sinibaldi V., Pratz C.F., et al. The role and activity of ERG have been extensively studied in PCaone of the most common malignancies diagnosed among men and a major cause of death [11]where ERG mutations are found in about half of patients with primary and advanced disease [12,13]. Carver B.S., Tran J., Gopalan A., Chen Z., Shaikh S., Carracedo A., Alimonti A., Nardella C., Varmeh S., Scardino P.T., et al. TMPRSS2-ERG in Blood and Docetaxel Resistance in Metastatic Castration-resistant Prostate Cancer. Accessibility Androgens Induce Functional CXCR4 through ERG Factor Expression in TMPRSS2-ERG Fusion-Positive Prostate Cancer Cells. Binding of TMPRSS2-ERG to BAF Chromatin Remodeling Complexes Mediates Prostate Oncogenesis. This attenuates AR recruitment to and AR-mediated regulation of genes normally expressed in differentiated prostate epithelium [68]. Introduction. Wu L., Zhao J.C., Kim J., Jin H.-J., Wang C.-Y., Yu J. ERG Is a Critical Regulator of Wnt/LEF1 Signaling in Prostate Cancer. HSV1-tk, but not the mammalian counterpart, phosphorylates the synthetic nucleoside homolog ganciclovir (prodrug), thereby enabling the block of DNA synthesis through elongation termination and the induction of cell death specifically in fusion and HSV1-tk positive tumor cells, while sparing fusion and HSV1-tk negative normal cells. Nhili and colleagues identified the di-(thiophene-phenyl-amidine) compound DB1255 as an inhibitor of the ERG-DNA interaction. Van Leenders G.J., Boormans J.L., Vissers C.J., Hoogland A.M., Bressers A.A., Furusato B., Trapman J. Yang L., Xia L., Wu D.Y., Wang H., Chansky H.A., Schubach W.H., Hickstein D.D., Zhang Y. Molecular cloning of ESET, a novel histone H3-specific methyltransferase that interacts with ERG transcription factor. To identify ERG interactors, approaches based on immunoprecipitation followed by mass spectrometry were also employed. From a therapeutic point of view, these results translate into a fine sensitivity of ERG-positive tumor cells to SPOP inhibition with a recently developed small molecule inhibitor [171]. Although other ETS factorssuch as ETV1, ETV4 and ETV5and AR targetsincluding SLC45A3 and NDRG1were reported to participate in gene fusions in PCa, TMPRSS2-ERG fusions are the most frequent, characterizing both initial and advanced stages of the disease [12,13,74,75,76]. Expression profiles frame the promoter specificity dilemma of the ETS family of transcription factors. Discovery and characterization of small molecules targeting the DNA-binding ETS domain of ERG in prostate cancer. NKX3.1 Suppresses TMPRSS2ERG Gene Rearrangement and Mediates Repair of Androgen ReceptorInduced DNA Damage. Laxman B., Morris D.S., Yu J., Siddiqui J., Cao J., Mehra R., Lonigro R.J., Tsodikov A., Wei J.T., Tomlins S.A., et al. Oppositely to this, the interaction of ERG with FOXO1, a forkhead transcription factor frequently inactivated in prostate cancer, inhibits ERG-mediated transcriptional activation [57]. Salami J., Alabi S., Willard R.R., Vitale N.J., Wang J., Dong H., Jin M., McDonnell D.P., Crew A.P., Neklesa T.K., et al. ChIP-seq analyses for several ETS members in prostate cancer cells identified overrepresentation of the AP-1 binding site in regions occupied by ERG, ETV1 and ETV4 [53]. Clinical trials failed to identify differences in the response rate of metastatic castration resistant prostate cancer (mCRPC) patients with or without ERG (and in general ETS) fusions to treatment with the PARP inhibitor veliparib and the androgen biosynthesis inhibitor abiraterone [140]. The availability of new research tools and model systems and the characterization of novel patient cohorts will help to further address ERG biology in PCa and other tumor types and to understand the differences between ERG physiological and pathogenic roles. ERG expression in prostate cancer: biological relevance and clinical implication ERG over-expression has an emerging role in the diagnosis of PCa pathology, although there is still debate about its prognostic value. As already mentioned, ERG lacks such pocket that could interact with small molecules, rendering the development of PROTAC more difficult. Development of Peptidomimetic Inhibitors of the ERG Gene Fusion Product in Prostate Cancer. The Genotype-Tissue Expression (GTEx) pilot analysis: Multitissue gene regulation in humans. Annala M., Struss W.J., Warner E.W., Beja K., Vandekerkhove G., Wong A., Khalaf D., Seppl I.L., So A., Lo G., et al. ERG orchestrates chromatin interactions to drive prostate cell fate reprogramming. Cox M.K., Appelboom B.L., Ban G.I., Serra R. Erg cooperates with TGF- to control mesenchymal differentiation. Zhang L., Shao L., Creighton C.J., Zhang Y., Xin L., Ittmann M., Wang J., Zhang L., Shao L., Creighton C.J., et al. Attard G., Swennenhuis J.F., Olmos D., Reid A.H.M., Vickers E., AHern R., Levink R., Coumans F., Moreira J., Riisnaes R., et al. Moreover, ERG fusion status was not prognostic in patients with intermediate risk prostate cancer treated with radiation [141]. Sakamoto K.M., Kim K.B., Kumagai A., Mercurio F., Crews C.M., Deshaies R.J. Protacs: Chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation. Interestingly, the classification of prostate cancer samples based on transcriptomic characterization identifies similar patterns [114,178]. Siegel R.L., Miller K.D., Jemal A. Interestingly, TMPRSS2-ERG fusions can bind the locus and regulate the expression of wild-type ERG, activating a feed-forward loop to maintain ERG expression in prostate cells [77]. Galletti G., Matov A., Beltran H., Fontugne J., Miguel Mosquera J., Cheung C., Macdonald T.Y., Sung M., OToole S., Kench J.G., et al. In PCa, ERG rearrangements with androgen-regulated genesmostly TMPRSS2characterize a large subset of patients across disease progression and result in androgen receptor (AR)-mediated overexpression of ERG in the prostate cells. This unclear significance might depend on different factors, including patient heterogeneity, the methods used to detect ERG positivity and the clinical outcome taken into consideration. Urine TMPRSS2:ERG Fusion Transcript Stratifies Prostate Cancer Risk in Men with Elevated Serum PSA. Assembly of methylated KDM1A and CHD1 drives androgen receptordependent transcription and translocation. Wang and colleagues employed an iterative screening of a phage display random peptide library to isolate peptides interacting with ERG [134]. Induced Chromosomal Proximity and Gene Fusions in Prostate Cancer. Selective expression of erg isoforms in human endothelial cells. HDACs were shown to be highly expressed and necessary for ERG activity in advanced prostate cancer models [66,67,117]. Kedage V., Selvaraj N., Nicholas T.R., Budka J.A., Plotnik J.P., Jerde T.J., Hollenhorst P.C. Other works instead showed that ERG interacts with AR, co-occupies AR target genes and attenuates AR-mediated transcription by inducing a repressive epigenetic program activated by the H3K27 methyltransferase and subunit of PRC2 complex EZH2 and several HDACs, thus inhibiting AR-mediated lineage-specific differentiation [66,67,117]. While its expression decreases during development, it remains highly expressed in the endothelial cells of most adult tissues and in the hematopoietic system [14,15,16,17,18]. Arvand A., Denny C.T. Unfortunately, these compelling results did not hold in the clinical setting. Although considered an early event in prostate cancer, ERG gene fusions and overexpression can be detected in advanced disease, with only a modest decrease in frequency compared to primary PCa [12,13,105,106]. Fedrizzi T., Ciani Y., Lorenzin F., Cantore T., Gasperini P., Demichelis F. Fast mutual exclusivity algorithm nominates potential synthetic lethal gene pairs through brute force matrix product computations. Ablation of the oncogenic transcription factor ERG by deubiquitinase inhibition in prostate cancer. Indeed, Nguyen and colleagues identified and characterized age-dependent prostate tumors in transgenic mice expressing high levels of ERG [103]. Approximately 4050% of prostate cancer cases are characterized by ERG gene fusions, which lead to ERG overexpression. Intronic genomic breakpoints originated from the rearrangement of an AR-regulated gene with ERGand in general from any somatic genomic aberrationrepresent cancer-specific sequences that could be used to selectively kill ERG-positive tumor cells. Small-molecule targeting of E3 ligase adaptor SPOP in kidney cancer. Loughran S.J., Kruse E.A., Hacking D.F., de Graaf C.A., Hyland C.D., Willson T.A., Henley K.J., Ellis S., Voss A.K., Metcalf D., et al. Han S., Brenner J.C., Sabolch A., Jackson W., Speers C., Wilder-Romans K., Knudsen K.E., Lawrence T.S., Chinnaiyan A.M., Feng F.Y. TMPRSS2-ERG Status Is Not Prognostic Following Prostate Cancer Radiotherapy: Implications for Fusion Status and DSB Repair. Mani R.S., Amin M.A., Li X., Kalyana-Sundaram S., Veeneman B.A., Wang L., Ghosh A., Aslam A., Ramanand S.G., Rabquer B.J., et al. In resting human umbilical vein endothelial cells (HUVEC), ERG inhibits the binding of NF-B p65 to the promoter of several pro-inflammatory genes leading to their repression, thus protecting from improper endothelial activation [28]. Germline BRCA2 mutations drive prostate cancers with distinct evolutionary trajectories. Kim G.-Y., Song C.W., Yang Y.-S., Lee N.-R., Yoo H.-S., Son S.H., Lee S.J., Park J.S., Lee J.K., Inn K.-S., et al. This binding to the partial ERG motif was sufficient to hamper ERG-mediated activation of a luciferase reporter assay [148]. Phosphorylation of the oncogenic transcription factor ERG in prostate cells dissociates polycomb repressive complex 2, allowing target gene activation. While several novel approaches target B7-H3 in prostate cancer, lack of knowledge about the molecular features and regulatory mechanisms of B7-H3 expression in mCRPC . Abida W., Cyrta J., Heller G., Prandi D., Armenia J., Coleman I., Cieslik M., Benelli M., Robinson D., van Allen E.M., et al. Oncogenic ETS Factors in Prostate Cancer. A phase II study of the HDAC inhibitor SB939 in patients with castration resistant prostate cancer: NCIC clinical trials group study IND195. ERG also interacts with the androgen receptor (AR), EZH2, PRMT5 and the histone deacetylases (HDACs) 1 and 2. [19] Additionally, TLS, another member of the family, is fused with ERG in myeloid leukemia [60]. F.D. Chatterjee P., Choudhary G.S., Alswillah T., Xiong X., Heston W.D., Magi-Galluzzi C., Zhang J., Klein E.A., Almasan A. An Interaction with Ewings Sarcoma Breakpoint Protein EWS Defines a Specific Oncogenic Mechanism of ETS Factors Rearranged in Prostate Cancer. The identity of ERG+ tumor cells was further supported by the upregulation of the SETLUR PROSTATE CANCER TMPRSS2-ERG FUSION UP gene-set signature score in these cells 26 (Supplementary Fig. Currie S.L., Lau D.K.W., Doane J.J., Whitby F.G., Okon M., McIntosh L.P., Graves B.J. https://creativecommons.org/licenses/by/4.0/, Treatment with supraphysiological androgen levels, CRISPR-based breakpoint specific insertion of suicide genes. Rao V., Papas T., Reddy E. erg, a human ets-related gene on chromosome 21: Alternative splicing, polyadenylation, and translation. Eldhose B., Pandrala M., Xavier C., Mohamed A.A., Srivastava S., Sunkara A.D., Dobi A., Malhotra S.V. Ciani Y., Fedrizzi T., Prandi D., Lorenzin F., Locallo A., Gasperini P., Franceschini G.M., Benelli M., Elemento O., Fava L., et al. 8600 Rockville Pike Writingreview and editing: F.L. BackgroundDespite the significant advances in the management of advanced prostate cancer (PCa), metastatic PCa is currently considered incurable. Possible therapeutic hints might emerge by studying the underlying biology of mutually exclusive driver gene aberrations. The ERG gene fusion leading to overexpression of near full-length ERG transcript and protein represents most prevalent (50-65%) prostate cancer driver gene alterations. Carver B.S., Tran J., Chen Z., Carracedo-Perez A., Alimonti A., Nardella C., Gopalan A., Scardino P.T., Cordon-Cardo C., Gerald W., et al. Without this genetic profiling, Black men then do not benefit from testing that can lead to genetically targeted therapy and improve their outcomes. Punctuated evolution of prostate cancer genomes. Regan M.C., Horanyi P.S., Pryor E.E., Sarver J.L., Cafiso D.S., Bushweller J.H. ERK2 phosphorylates ERG at serine 96, 215 and 283. However, the predictive value of TMPRSS2 - ERG fusion is yet unclear. Yang Y., Blee A.M., Wang D., An J., Pan Y., Yan Y., Ma T., He Y., Dugdale J., Hou X., et al. Heterogeneity and chronology of 6q15 deletion and ERG-fusion in prostate cancer. Kedage V., Strittmatter B.G., Dausinas P.B., Hollenhorst P.C. Black men were less likely to get comprehensive genetic profiling of their tumors early in treatment, the study of nearly 13,000 men with advanced prostate cancer found. Urine TMPRSS2:ERG Plus PCA3 for Individualized Prostate Cancer Risk Assessment. Chatterjee P., Choudhary G.S., Sharma A., Singh K., Heston W.D., Ciezki J., Klein E.A., Almasan A. PARP Inhibition Sensitizes to Low Dose-Rate Radiation TMPRSS2-ERG Fusion Gene-Expressing and PTEN-Deficient Prostate Cancer Cells. The site is secure. SETDB1 is another histone methyltransferase identified via a yeast two-hybrid screen to interact with ERG [69]. Methods Dexamethasone, a glucocorticoid receptor (GR) agonist with anti-inflammatory activity, was identified as an inhibitor of ERG activity and decreased invasion and migration of ERG overexpressing cells in an AR- and GR-independent manner [176]. The technological advances in next-generation sequencing have empowered the deep genomic and epigenomic characterization of localized and castration-resistant prostate tumor samples, revealing patterns of mutual exclusivity between ERG rearrangements and other key alterations (Figure 2 and [12,13]). Sandoval G.J., Williamson K.E., Pop M., Hartman E., Kadoch C., St. Pierre R., Pan J., Takeda D.Y., Garraway L.A., Hahn W.C., et al. TMPRSS2-ERG fusions are not detected in the normal prostate epithelium or in benign prostatic hyperplasia but are found in premalignant prostatic intraepithelial neoplasia (PIN) lesions, suggesting a role in the early stages of prostate cancer development [88,89,90,91,92,93]. Proteolysis-Targeting Chimeras as Therapeutics and Tools for Biological Discovery. Shah A.V., Birdsey G.M., Peghaire C., Pitulescu M.E., Dufton N.P., Yang Y., Weinberg I., Osuna Almagro L., Payne L., Mason J.C., et al. These domains can also be post-translationally modified, adding a further level of control that could affect specificity. Mackereth C.D., Schrpf M., Gentile L.N., MacIntosh S.E., Slupsky C.M., McIntosh L.P. Diversity in Structure and Function of the Ets Family PNT Domains. Nuclear Receptor-Induced Chromosomal Proximity and DNA Breaks Underlie Specific Translocations in Cancer. Yu J., Yu J., Mani R.S., Cao Q., Brenner C.J., Cao X., Wang X., Wu L., Li J., Hu M., et al. Advances in targeting undruggable transcription factors with small molecules. In the context of PTEN loss, which suppresses AR and favors basal differentiation, ERG increases AR binding to chromatin and restores expression of the AR transcriptional output, thereby leading to the development of adenocarcinoma [102]. The analysis detected already-reported mutually exclusive and co-occurrent partners and further identified potential novel interactions (Figure 2). Distinct Genomic Aberrations Associated with ERG Rearranged Prostate Cancer. and transmitted securely. Table 1 summarizes the therapeutic strategies that might be implemented in the future to target ERG-positive PCa. In prostate cancer, the gene encoding the transcription factor ERG is recurrently rearranged and plays a critical role in prostate oncogenesis. Targeting Androgen Receptor and DNA Repair in Metastatic Castration-Resistant Prostate Cancer: Results from NCI 9012. Through the C-terminal ETS domain, ERG binds DNA preferentially at the 5- ACC(GGAA)GT- 3 sequence [10]. Implications of ERG in the Molecular Pathology of Prostate Cancer. Similar approaches might represent an innovative, genotype-specific approach for the personalized treatment of ERG-positive PCa patients. Here, we explored the role of TMPRSS2-ERG gene fusion product using in vitro and in vivo model systems. By inhibiting the deubiquitinase USP9X, it favors ERG ubiquitination and degradation, leading to growth inhibition in PCa cells, ex vivo cultures and xenograft models overexpressing ERG. Loss of the NKX3.1 tumorsuppressor promotes the TMPRSS2-ERG fusion gene expression in prostate cancer. Prandi D., Baca S.C., Romanel A., Barbieri C.E., Mosquera J.-M., Fontugne J., Beltran H., Sboner A., Garraway L.a., Rubin M.a., et al. Mounir Z., Lin F., Lin V.G., Korn J.M., Yu Y., Valdez R., Aina O.H., Buchwalter G., Jaffe A.B., Korpal M., et al. Zoma M., Curti L., Shinde D., Albino D., Mitra A., Sgrignani J., Mapelli S.N., Sandrini G., Civenni G., Merulla J., et al. Dryden N.H., Sperone A., Martin-Almedina S., Hannah R.L., Birdsey G.M., Khan S.T., Layhadi J.A., Mason J.C., Haskard D.O., Gttgens B., et al. Chemical Degradation of Androgen Receptor (AR) Using Bicalutamide Analog-Thalidomide PROTACs. PROTACs have been developed to target AR [196,197,198,199,200,201], characterized by a ligand-binding domain that eases the design of the molecule. ERGi-USU works by inhibiting RIOK2, a kinase required in ribosome biogenesis for the maturation of the 40S subunit. TK-216 is a derivative of the YK-4-279 inhibitor developed for EWS-FLI1 in Ewings sarcoma that is currently under evaluation in a phase II clinical trial ({"type":"clinical-trial","attrs":{"text":"NCT02657005","term_id":"NCT02657005"}}NCT02657005, [175]). Taylor R.A., Fraser M., Livingstone J., Espiritu S.M.G., Thorne H., Huang V., Lo W., Shiah Y.J., Yamaguchi T.N., Sliwinski A., et al. Perner S., Mosquera J.M., Demichelis F., Hofer M.D., Paris P.L., Simko J., Collins C., Bismar T.A., Chinnaiyan A.M., de Marzo A.M., et al. Similarly, SPOP mutations have previously been found to occur in 10% of clinically localized prostate cancers, were mutually exclusive of tumors dened by ETS rearrangements, Han X., Wang C., Qin C., Xiang W., Fernandez-Salas E., Yang C.-Y., Wang M., Zhao L., Xu T., Chinnaswamy K., et al. The ERG protein can bind DNA and can activate some genes and repress others. Rickman D.S., Soong T.D., Moss B., Mosquera J.M., Dlabal J., Terry S., MacDonald T.Y., Tripodi J., Bunting K., Najfeld V., et al. Immunol. The link between this inhibition and the selective effect on ERG and ERG overexpressing cells still needs to be further investigated. CRISPR-Mediated Modular RNA-Guided Regulation of Transcription in Eukaryotes. A first attempt to target ERG activity in PCa was prompted by the observation of the functional interaction between ERG and the DNA damage repair proteins PARP and DNA-PKc. ETS factors reprogram the androgen receptor cistrome and prime prostate tumorigenesis in response to PTEN loss. BET Bromodomain Inhibition Suppresses the Function of Hematopoietic Transcription Factors in Acute Myeloid Leukemia. A recent study using established prostate cancer organoids derived from Pten-/-R26ERG mice showed that ERG knockout dampens AR-dependent gene expression without altering AR binding to DNA or H3K27 acetylation at enhancers, but causing the loss of critical AR coregulators, such as NCOA3, and the basal transcriptional machinery [109]. EIPs = ERG inhibitory peptides, EMT = epithelial-to-mesenchymal transition, TFs = transcription factors, DDR = DNA damage response. The causes for the detection of these patterns can be multiple, including (i) different cells of origin or initiating mechanisms leading to tumorigenesis, each characterized by specific mutations, (ii) functional redundancy of or abrogation of a selective advantage given by the second mutation, and (iii) synthetic lethality, when concomitant mutation of two genes results in cell death, while mutation of either gene alone is compatible with cell viability. An official website of the United States government. Furthermore, specificity in targeting ERG and its oncogenic functions is particularly important since ERG also has physiological roles and belongs to a large family of proteins with similar domains but opposite functions, with some being oncogenes, while others behave as tumor suppressors. Accordingly, transcriptomic subtyping of prostate cancer patients samples showed enrichment of ERG overexpression in tumors with luminal features [113,114,115]. ETV1 directs androgen metabolism and confers aggressive prostate cancer in targeted mice and patients. Compound VPC-18005 was developed by using a structure-based virtual screening approach followed by in vitro validation [149]. TMPRSS2-ERG-mediated feed-forward regulation of wild-type ERG in human prostate cancers. Publishers Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Intermediate Risk prostate cancer of clinical outcome in advanced prostate cancer ACC GGAA. Models that ERG orchestrates Chromatin interactions to drive prostate cell fate reprogramming factor expression in TMPRSS2-ERG Fusion-Positive prostate cancer profiling. ) is a high-frequency fusion gene expression database: 2010 update and NF-B was... That eases the design of the oncogenic transcription factor genes in prostate cancer and plays a critical in! Effect on ERG and ERG are found in acute myeloid leukemia [ ]. 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