Abstract
Simple SummaryIn addition to its role in development and in the vascular and hematopoietic systems, ERG plays a central role in prostate cancer. Approximately 40–50% of prostate cancer cases are characterized by ERG gene fusions, which lead to ERG overexpression. Importantly, inhibition of ERG activity in prostate cancer cells decreases their viability. Therefore, inhibiting ERG might represent an important step to improve treatment efficacy for patients with ERG-positive prostate tumors. 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.The ETS family member ERG is a transcription factor with physiological roles during development and in the vascular and hematopoietic systems. ERG oncogenic activity characterizes several malignancies, including Ewing’s sarcoma, leukemia and prostate cancer (PCa). In PCa, ERG rearrangements with androgen-regulated genes—mostly TMPRSS2—characterize a large subset of patients across disease progression and result in androgen receptor (AR)-mediated overexpression of ERG in the prostate cells. Importantly, PCa cells overexpressing ERG are dependent on ERG activity for survival, further highlighting its therapeutic potential. Here, we review the current understanding of the role of ERG and its partners in PCa. 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.
Highlights
Introduction28 members encoded by the human genome [1,2]. E-26 transformation-specific (ETS) members are defined by a conserved 85 amino acid-long ETS domain that binds DNA over a region of 15–20 base pairs with a core 5 -GGA(A/T)-3 sequence [3]
The E-26 transformation-specific (ETS) family of transcription factors includes28 members encoded by the human genome [1,2]
TMPRSS2ERG fusion can serve as cancer-specific biomarker for early diagnosis of prostate cancer (PCa) and can be detected in urine samples via reverse transcription–polymerase chain reaction (RT-PCR) or a clinical-grade transcription-mediated amplification (TMA) assay [162–167]
Summary
28 members encoded by the human genome [1,2]. ETS members are defined by a conserved 85 amino acid-long ETS domain that binds DNA over a region of 15–20 base pairs with a core 5 -GGA(A/T)-3 sequence [3]. Methylated K362 changes the intra-domain interaction between the ETS domain, where K362 is located, and the C-terminal inhibitory domain increasing accessibility and favoring binding to DNA, with consequent enhanced ERG transcriptional and oncogenic activity [52]. ERG in conjunction with p300 activity recruits BRD4 at its target genes, leading to their transcriptional activation and supporting leukemia maintenance and prostate cancer cell invasion [62,63]. By using immunoprecipitation followed by stable isotope labelling with amino acids in cell culture (SILAC)-based proteomic mass spectrometry, the Kadoch’s laboratory revealed the direct interaction of ERG with components of the mammalian SWI/SNF (BAF) complex [59] They further showed that ERG recruits BAF complexes to sites enriched for ETS motifs and that BAF complex activity is required for global ERG chromatin occupancy and target gene regulation. The relevance of this interaction for ERG biology is currently unknown but might be related to SETDB1-mediated gene silencing and maintenance of pluripotency [70,71]
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