Androgen-Dependent Oncogenic Activation of ETS Transcription Factors by Recurrent Gene Fusions in Prostate Cancer: Biological and Clinical Implications

2013 ◽  
pp. 307-328 ◽  
Author(s):  
Albert Dobi ◽  
Taduru Sreenath ◽  
Shiv Srivastava
Keyword(s):  
Prostate Cancer ◽  
Transcription Factors ◽  
Clinical Implications ◽  
Gene Fusions ◽  
Ets Transcription Factors ◽  
Recurrent Gene Fusions

scholarly journals ETS fusion genes in prostate cancer

2014 ◽  
Vol 21 (3) ◽  
pp. R143-R152 ◽  
Author(s):  
Delila Gasi Tandefelt ◽  
Joost Boormans ◽  
Karin Hermans ◽  
Jan Trapman
Keyword(s):  
Prostate Cancer ◽  
Transcription Factors ◽  
Current Knowledge ◽  
Tumor Development ◽  
Developed Countries ◽  
Genomic Alteration ◽  
Gene Fusions ◽  
Ets Transcription Factors ◽  
Progressive Growth

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 prostate-specific. 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.

scholarly journals RNA-seq analysis of prostate cancer in the Chinese population identifies recurrent gene fusions, cancer-associated long noncoding RNAs and aberrant alternative splicings

Cell Research ◽  
2012 ◽  
Vol 22 (5) ◽  
pp. 806-821 ◽  
Author(s):  
Shancheng Ren ◽  
Zhiyu Peng ◽  
Jian-Hua Mao ◽  
Yongwei Yu ◽  
Changjun Yin ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Chinese Population ◽  
Noncoding Rnas ◽  
Long Noncoding Rnas ◽  
Gene Fusions ◽  
Rna Seq ◽  
Recurrent Gene Fusions

scholarly journals Electrostatic repulsion causes anticooperative DNA binding between tumor suppressor ETS transcription factors and JUN-FOS at composite DNA sites

2018 ◽  
Author(s):  
Bethany J. Madison ◽  
Kathleen A. Clark ◽  
Niraja Bhachech ◽  
Peter C. Hollenhorst ◽  
Barbara J. Graves ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Transcription Factors ◽  
Dna Binding ◽  
Dna Sequences ◽  
Binding Sites ◽  
Epithelial Cell Line ◽  
Electrostatic Repulsion ◽  
Ets Transcription Factors ◽  
Positively Charged

AbstractMany transcription factors regulate gene expression in a combinatorial fashion often by binding in close proximity on composite cis-regulatory DNA elements. Here we investigate the molecular basis by which ETS transcription factors bind with AP1 transcription factors JUN-FOS at composite DNA-binding sites. The ability to bind to DNA with JUN-FOS correlates with the phenotype of these proteins in prostate cancer: the oncogenic ERG and ETV1/4/5 subfamilies co-occupy ETS-AP1 sites with JUN-FOS in vitro, whereas JUN-FOS robustly inhibits DNA binding by the tumor suppressors EHF and SPDEF. EHF binds to ETS-AP1 DNA with tighter affinity than ERG in the absence of JUN-FOS, which may enable EHF to compete with ERG and JUN-FOS for binding to ETS-AP1 sites. Genome-wide mapping of EHF and ERG binding sites in a prostate epithelial cell line reveal that EHF is preferentially excluded from closely spaced ETS-AP1 DNA sequences. Structural modeling and mutational analyses indicate that adjacent positively-charged surfaces from EHF and JUN-FOS disfavor simultaneous DNA binding due to electrostatic repulsion. The conservation of positively charged residues on the JUN-FOS interface identified ELF1 as an additional ETS factor that exhibits anticooperative DNA binding, and we present evidence that ELF1 is frequently downregulated in prostate cancer. In summary, the divergence of electrostatic features of ETS factors at their JUN-FOS interface enables distinct binding events at ETS-AP1 DNA sequences. We propose that this mechanism can drive unique targeting of ETS transcription factors, thereby facilitating distinct transcriptional programs.

scholarly journals RNA-seq analysis of prostate cancer in the Chinese population identifies recurrent gene fusions, cancer-associated long noncoding RNAs and aberrant alternative splicings

Cell Research ◽  
2013 ◽  
Vol 23 (5) ◽  
pp. 732-732 ◽  
Author(s):  
Shancheng Ren ◽  
Zhiyu Peng ◽  
Jian-Hua Mao ◽  
Yongwei Yu ◽  
Changjun Yin ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Chinese Population ◽  
Noncoding Rnas ◽  
Long Noncoding Rnas ◽  
Gene Fusions ◽  
Rna Seq ◽  
Recurrent Gene Fusions

scholarly journals ETS Transcription Factors Control Transcription of EZH2 and Epigenetic Silencing of the Tumor Suppressor Gene Nkx3.1 in Prostate Cancer

PLoS ONE ◽  
2010 ◽  
Vol 5 (5) ◽  
pp. e10547 ◽  
Author(s):  
Paolo Kunderfranco ◽  
Maurizia Mello-Grand ◽  
Romina Cangemi ◽  
Stefania Pellini ◽  
Afua Mensah ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Transcription Factors ◽  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Suppressor Gene ◽  
Epigenetic Silencing ◽  
Ets Transcription Factors

scholarly journals ERG upregulation and related ETS transcription factors in prostate cancer

2007 ◽  
Author(s):  
Kari Rostad ◽  
Monica Mannelqvist ◽  
Ole Halvorsen ◽  
Anne Øyan ◽  
Trond Bø ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Transcription Factors ◽  
Ets Transcription Factors

Detection of novel variant TMPRSS2 /ERG fusion transcripts suggests independent genomic alterations may underlie origin of multi-centric prostate cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 10029-10029
Author(s):  
M. Yoshimoto ◽  
A. M. Joshua ◽  
S. Chilton-Macneill ◽  
J. Bayani ◽  
M. Prasad ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Transcription Factors ◽  
Fusion Gene ◽  
Fusion Transcript ◽  
Functional Protein ◽  
Ets Transcription Factors ◽  
Fusion Transcripts ◽  
Novel Variant ◽  
Exon 1 ◽  
Prostate Cancers

10029 Background: Most of the early successes in identifying chromosomal translocations in neoplasias came from the study of hematological malignancies and sarcomas, with limited evidence that consistent genomic rearrangements were present in epithelial malignancies. Recently it was reported that ∼75% of prostate cancers carry a genomic rearrangement leading to fusion of the TMPRSS2 locus to either the ERG or ETV1 genes (both ETS transcription factors). In the fusion gene, the androgen-sensitive promoter elements of TMPRSS2 are thought to mediate over-expression of these ETS transcription factors. Over-activity of the ETS family of transcription factors has been suggested to be involved in the transition from pre-neoplasia to carcinoma as they regulate genes involved in processes such as adhesion, motility, invasion and angiogenesis. Methods: Using both RT-PCR and FISH with published primers and BACs respectively we analyzed 15 samples of prostatic carcinoma from radical prostatectomies and sequenced a subset of the TMPRSS2/ERG fusions. Results: We have found ERG-TMPRSS2 fusion transcripts in 6 samples and no ETV1-TMPRSS2 fusions. Of the 6 fusion tumours, 5 were Gleason 7 and 1 was Gleason 9. Tumour stages ranged from T2a-T3b. One sample with multi-centric carcinoma exhibited 2 distinct in-frame rearrangements generating novel TMPRSS2 /ERG fusion transcripts. Variant I TMPRSS2/ERG transcript was 430 bp and it led to fusion of exons 1 and 2 of the TMPRSS2 gene with exons 5 and 6 of the ERG gene. Variant II TMPRSS2/ERG fusion transcript was slightly smaller at 350 bp and it led to fusion of exon 1 of the TMPRSS2 gene to exons 5 and 6 of the ERG gene. These novel transcripts appear to be smaller than the published fusion proteins but preliminary analysis suggests that all known regulatory and functional protein domains are maintained. Conclusions: The demonstration of two new TMPRSS2/ERG variant fusion transcripts in prostate cancer deserves further study to evaluate their functional impact and prognostic and pathological importance. Moreover the presence of two distinct transcripts within a single multi-centric tumor provides genomic evidence that independent clonal neoplasms can arise synchronously in prostate cancer. No significant financial relationships to disclose.

scholarly journals Development of High-Throughput Screening Assays for Inhibitors of ETS Transcription Factors

2018 ◽  
Vol 24 (1) ◽  
pp. 77-85
Author(s):  
Simon L. Currie ◽  
Steven L. Warner ◽  
Hariprasad Vankayalapati ◽  
Xiaohui Liu ◽  
Sunil Sharma ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Transcription Factors ◽  
High Throughput ◽  
High Throughput Screening ◽  
In Vitro Assays ◽  
Ets Transcription Factors ◽  
Virtual Screen ◽  
Prostate Cells ◽  
Screening Assays

ETS transcription factors from the ERG and ETV1/4/5 subfamilies are overexpressed in the majority of prostate cancer patients and contribute to disease progression. Here, we have developed two in vitro assays for the interaction of ETS transcription factors with DNA that are amenable to high-throughput screening. Using ETS1 as a model, we applied these assays to screen 110 compounds derived from a high-throughput virtual screen. We found that the use of lower-affinity DNA binding sequences, similar to those that ERG and ETV1 bind to in prostate cells, allowed for higher inhibition from many of these test compounds. Further pilot experiments demonstrated that the in vitro assays are robust for ERG, ETV1, and ETV5, three of the ETS transcription factors that are overexpressed in prostate cancer.

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