Mechanistic Rationale for Inhibition of Poly(ADP-Ribose) Polymerase in ETS Gene Fusion-Positive Prostate Cancer

Brenner, J. Chad; Ateeq, Bushra; Li, Yong; Yocum, Anastasia K.; Cao, Qi; Asangani, Irfan A.; Patel, Sonam; Wang, Xiaoju; Liang, Hallie; Yu, Jindan; Palanisamy, Nallasivam; Siddiqui, Javed; Yan, Wei; Cao, Xuhong; Mehra, Rohit; Sabolch, Aaron; Basrur, Venkatesha; Lonigro, Robert J.; Yang, Jun; Tomlins, Scott A.; Maher, Christopher A.; Elenitoba-Johnson, Kojo S.J.; Hussain, Maha; Navone, Nora M.; Pienta, Kenneth J.; Varambally, Sooryanarayana; Feng, Felix Y.; Chinnaiyan, Arul M.

doi:10.1016/j.ccr.2011.04.010

Cited by 380 publications

(332 citation statements)

References 53 publications

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“…In a recent report two independent cohorts of over 100 patients were treated with external beam radiotherapy (Dal Pra et al 2013). Although preclinical studies predicted that TMPRSS2-ERG tumors might be more sensitive to radiation (Brenner et al 2011), the presence of the gene fusion showed no association with biochemical recurrence-free survival in the clinical study. So, a simple extrapolation of experimental data to the clinical setting seems not to be possible and other factors not included in the clinical analyses so far contribute to clinical behavior.…”

Section: Ets Fusions As Diagnostic and Prognostic Markers Of Prostatementioning

confidence: 99%

ETS fusion genes in prostate cancer

Tandefelt¹,

Boormans²,

Hermans³

et al. 2014

Endocrine-Related Cancer

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Prostate cancer is very common in elderly men in developed countries. Unravelling the molecular and biological processes that contribute to tumor development and progressive growth, including its heterogeneity, is a challenging task. The fusion of the genes ERG and TMPRSS2 is the most frequent genomic alteration in prostate cancer. ERG is an oncogene that encodes a member of the family of ETS transcription factors. At lower frequency, other members of this gene family are also rearranged and overexpressed in prostate cancer. TMPRSS2 is an androgen-regulated gene that is preferentially expressed in the prostate. Most of the less frequent ETS fusion partners are also androgen-regulated and prostatespecific. During the last few years, novel concepts of the process of gene fusion have emerged, and initial experimental results explaining the function of the ETS genes ERG and ETV1 in prostate cancer have been published. In this review, we focus on the most relevant ETS gene fusions and summarize the current knowledge of the role of ETS transcription factors in prostate cancer. Finally, we discuss the clinical relevance of TMRPSS2-ERG and other ETS gene fusions in prostate cancer.

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Section: Ets Fusions As Diagnostic and Prognostic Markers Of Prostatementioning

confidence: 99%

ETS fusion genes in prostate cancer

Tandefelt¹,

Boormans²,

Hermans³

et al. 2014

Endocrine-Related Cancer

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show abstract

“…The ERG transcription factor encoded by TMPRSS2-ERG fusion is known to drive cell invasion and metastases, induce DNA damage in vitro, and focal pre-cancerous prostatic intraepithelial neoplasia (PIN) lesions in transgenic mice (8,9).…”

Section: Introductionmentioning

confidence: 99%

Epigenetic silencing of miRNA-338-5p and miRNA-421 drives SPINK1-positive prostate cancer

Bhatia

Yadav

Tiwari

et al. 2018

Preprint

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PurposeSerine Peptidase Inhibitor, Kazal type-1 (SPINK1) overexpression defines the second most recurrent and aggressive prostate cancer (PCa) subtype. However, the underlying molecular mechanism and pathobiology of SPINK1 in PCa remains largely unknown.Experimental DesignMicroRNA-prediction tools were employed to examine the SPINK1-3’UTR for miRNAs binding. Luciferase reporter assays were performed to confirm the SPINK1-3’UTR binding of shortlisted miR-338-5p/miR-421. Further, miR-338-5p/-421 overexpressing cancer cells (SPINK1-positive) were evaluated for oncogenic properties using cell-based functional assays and mice xenograft model. Global gene expression profiling was performed to unravel the biological pathways altered by miR-338-5p/-421. Immunohistochemistry and RNA in-situ hybridization was carried-out on PCa patients’ tissue microarray for SPINK1 and EZH2 expression respectively. Chromatin immunoprecipitation assay was performed to examine EZH2 occupancy on the miR-338-5p/-421 regulatory regions. Bisulfite sequencing and methylated DNA-immunoprecipitation was performed on PCa cell lines and patients’ specimens.ResultsWe established a critical role of miRNA-338-5p/-421 in post-transcriptional regulation of SPINK1. Ectopic expression of miRNA-338-5p/-421 in SPINK1-positive PCa cells abrogate oncogenic properties including cell-cycle progression, stemness and drug resistance, and show reduced tumor burden and distant metastases in mice model. Importantly, we show SPINK1-positive PCa patients exhibit increased EZH2 expression, suggesting its role in miRNA-338-5p/-421 epigenetic silencing. Furthermore, presence of CpG dinucleotide DNA methylation marks on the regulatory regions of miR-338-5p/-421 in SPINK1-positive PCa cells and patients’ specimens confirms epigenetic silencing.ConclusionOur findings revealed that miRNA-338-5p/-421 are epigenetically silenced in SPINK1-positive PCa, while restoring the expression of these miRNAs using epigenetic drugs or synthetic mimics could abrogate SPINK1-mediated oncogenesis.TRANSLATIONAL IMPACTWe establish a regulatory model involving the functional interplay between SPINK1, miRNA-338-5p/miRNA-421 and EZH2, thereby, revealing hitherto unknown mechanism of SPINK1 up-regulation in SPINK1-positive subtype. Our findings provide a strong rationale for the development of potential therapeutic strategies for SPINK1-positive malignancies. We demonstrate that restoring miRNA-338-5p/miRNA-421 expression using epigenetic drugs including DNMTs inhibitors in combination with HDACs or HKMTs inhibitors or miRNA synthetic mimics in SPINK1-positive prostate cancer abrogate SPINK1-mediated oncogenicity. The major findings of this study will not only advance the prostate cancer field, but will also be valuable for treatment and disease management of other SPINK1-positive malignancies.

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“…If an oncogenic mechanism is discovered, previous work has reported that ERG interacts in a DNA-independent manner with the enzyme poly (ADP-ribose) polymerase 1 (PARP1). This provides a basis for the use of PARP1 inhibitors, and studies have shown inhibition of xenograft PA growth in ETS-positive, but not ETS-negative tumors [23]. While significant hurdles remain before clinical utility, the potential exists for the first directed therapy against SCC.…”

Section: Discussionmentioning

confidence: 99%

Urinary Cytomorphology and Clinical Correlates of Prostatic Small Cell Neuroendocrine Carcinoma

Toll

Ali²

2013

Acta Cytologica

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Background: Small cell carcinoma (SCC) of the prostate represents a rare form of prostatic carcinoma. While the tumor is often considered to arise from neuroendocrine proliferation or possibly dedifferentiation of an acinar carcinoma, the precise etiology remains uncertain. The diagnosis of prostatic SCC in urine has to date not been described. Methods: A retrospective review was performed at a tertiary-care hospital, and 3 patients with prostatic SCC in voided urinary specimens were identified. The following clinical data were collected for each case: age, gender, treatment and follow-up information, when available. Results: The patient age range was 70-86 years, all male. Two patients had known metastatic adenocarcinoma of the prostate, and 1 had recently presented with prostatic SCC. One patient with metastatic disease died shortly after diagnosis, the other was lost to follow-up. The third patient with a recent presentation has yet to have a treatment plan finalized. Conclusions: Our results highlight the importance of making this uncommon diagnosis as it may carry significant treatment and prognostic importance. Future work should hopefully clarify the role of ERG gene rearrangements in the pathogenesis of prostatic SCC, as there is a potential role here for targeted therapy.

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Mechanistic Rationale for Inhibition of Poly(ADP-Ribose) Polymerase in ETS Gene Fusion-Positive Prostate Cancer

Cited by 380 publications

References 53 publications

ETS fusion genes in prostate cancer

ETS fusion genes in prostate cancer

Epigenetic silencing of miRNA-338-5p and miRNA-421 drives SPINK1-positive prostate cancer

Urinary Cytomorphology and Clinical Correlates of Prostatic Small Cell Neuroendocrine Carcinoma

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