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In prostate cancer, the oncogenicity of transcription factor ERG is mediated, in part, by competition with another member of the ETS family, ERF. Opposing protein actions in tumour growth In prostate cancer, TMPRSS2 – ERG translocations are very frequent and lead to overexpression of ERG, which can trigger tumour growth. Rohit Bose and colleagues now show that another member of the ETS family, ERF, functions as a tumour suppressor in prostate cancer. ERF is lost in many tumours without TMPRSS2 – ERG translocations. ERF normally competes with other members of the ETS family for binding to DNA, and this function is disabled either by loss of ERF or increased levels of ERG. These findings shed further light on the opposing functions of ETS family proteins in tumorigenesis. Half of all prostate cancers are caused by the TMPRSS2–ERG gene-fusion, which enables androgens to drive expression of the normally silent E26 transformation-specific (ETS) transcription factor ERG in prostate cells 1 , 2 . Recent genomic landscape studies of such cancers 3 , 4 , 5 , 6 , 7 , 8 have reported recurrent point mutations and focal deletions of another ETS member, the ETS2 repressor factor ERF 9 . Here we show these ERF mutations cause decreased protein stability and mostly occur in tumours without ERG upregulation. ERF loss recapitulates the morphological and phenotypic features of ERG gain in normal mouse prostate cells, including expansion of the androgen receptor transcriptional repertoire, and ERF has tumour suppressor activity in the same genetic background of Pten loss that yields oncogenic activity by ERG . In the more common scenario of ERG upregulation, chromatin immunoprecipitation followed by sequencing indicates that ERG inhibits the ability of ERF to bind DNA at consensus ETS sites both in normal and in cancerous prostate cells. Consistent with a competition model, ERF overexpression blocks ERG-dependent tumour growth, and ERF loss rescues TMPRSS2–ERG -positive prostate cancer cells from ERG dependency. Collectively, these data provide evidence that the oncogenicity of ERG is mediated, in part, by competition with ERF and they raise the larger question of whether other gain-of-function oncogenic transcription factors might also inactivate endogenous tumour suppressors.

Aberrant polymorphonuclear neutrophil (PMN) accumulation in tissues induces chronic vascular diseases. Endothelial cells (ECs) regulate the access of PMNs into the tissue from the blood. However, the mechanisms that prevent PMNs from being activated and accumulating in the tissue, a hallmark of acute lung injury (ALI), remain elusive. We demonstrate that conditional deletion of Erg in ECs spontaneously alters the PMN transcriptome, which is enriched with genes that induce PMN recruitment, adhesion, activation, and \"do not eat me\" signals due to impaired synthesis of the deubiquitinase A20. Decreased A20 levels, in turn, activated the transcription factor NF-κB and the secretion of MIP2α (human homolog of IL-8) in ECs. EC-secreted MIP2α/IL-8 engaged the CXCR2 cascade on PMNs, leading to their activation and inflammatory injury. These findings were recapitulated in the lungs and blood of PMNs from patients dying of ALI. Overexpression of the A20 gene in ECs or pharmacological inhibition of CXCR2 on PMNs in iEC-Erg-/- mice rescued EC control of PMNs and tissue homeostasis, and enhanced mouse survival after pneumonia. Thus, the EC/Erg/A20 axis regulates PMN accumulation and hyperactivation in the lungs by inhibiting EC-mediated IL-8 activation of PMN CXCR2, thereby providing a potential target for neutrophilic inflammatory vascular diseases.

γ-glutamyl-hydrolase (GGH) is a ubiquitously-expressed enzyme that regulates intracellular folate metabolism for cell proliferation, DNA synthesis, and repair. Employing GGH immunohistochemistry on a tissue microarray with 12,427 prostate cancers, we found that GGH expression was negative to low in normal prostate epithelium, whereas 88.3% of our 10,562 interpretable cancers showed GGH expression. GGH staining was considered as low intensity in 49.6% and as high intensity in 38.6% of cancers. High GGH expression was linked to the TMPRSS2:ERG-fusion positive subset of cancers (p < 0.0001), advanced pathological tumor stage, and high Gleason grade (p < 0.0001 each). Further analysis revealed that these associations were merely driven by the subset of ERG-negative cancers, High GGH expression was weakly linked to early biochemical recurrence in ERG negative cancers (p < 0.0001) and independent from established histo-pathological parameters. Moreover, GGH expression was linked to features of genetic instability, including presence of recurrent deletions at 3p, 5q, 6q, and 10q (PTEN, p ≤ 0.01 each), as well as to accelerated cell proliferation as measured by Ki67 immunohistochemistry (p < 0.0001). In conclusion, the results of our study identify GGH as an ERG subtype specific molecular marker with modest prognostic relevance, which may have clinical relevance if analyzed in combination with other molecular markers.

Epigenetic changes have been reported to promote the development and progression of prostate cancer (PCa). Compared to normal prostate tissue, tumor samples from patients treated with androgen-deprivation therapy (ADT) show the hypermethylation of genes primarily implicated in PCa progression. A series of 90 radical prostatectomies was retrospectively analyzed. A total of 46 patients had undergone surgery alone (non-treated) and 44 had received ADT prior to surgery (treated). Promoter methylation analysis of the candidate genes possibly involved in PCa response to ADT (AR, ESR1, ESR2, APC, BCL2, CD44, CDH1, RASSF1, ZEB1) was conducted by pyrosequencing. The mRNA expression of differentially methylated genes was investigated by quantitative real-time PCR. Intratumoral microvessel density and ERG expression were also assessed using immunohistochemistry. A statistically significant difference in CD44 promoter methylation levels was found, with higher levels in the non-treated cases, which accordingly showed lower CD44 gene expression than the treated cases. Moreover, lower ESR1 methylation levels were associated with higher ERG expression, and the CD44 methylation levels were increased in ERG-overexpressing tumors, particularly in the treated cases. Our data suggest an interplay between ERG expression and the epigenetic modifications in key genes of prostate tumorigenesis, and that CD44 promoter methylation could serve as a promising molecular biomarker of PCa progression under androgen-deprived conditions.

Studies on a new conditional mouse model reveal that ETS transcription factors, which are often mutated in prostate cancer, cause transformation by altering the androgen-receptor cistrome, priming the prostate epithelium to respond to upstream signals such as PTEN loss. Studies of ETS-mediated prostate oncogenesis have been hampered by a lack of suitable experimental systems. Here we describe a new conditional mouse model that shows robust, homogenous ERG expression throughout the prostate. When combined with homozygous Pten loss, the mice developed accelerated, highly penetrant invasive prostate cancer. In mouse prostate tissue, ERG markedly increased androgen receptor (AR) binding. Robust ERG-mediated transcriptional changes, observed only in the setting of Pten loss, included the restoration of AR transcriptional output and upregulation of genes involved in cell death, migration, inflammation and angiogenesis. Similarly, ETS variant 1 (ETV1) positively regulated the AR cistrome and transcriptional output in ETV1 -translocated, PTEN -deficient human prostate cancer cells. In two large clinical cohorts, expression of ERG and ETV1 correlated with higher AR transcriptional output in PTEN -deficient prostate cancer specimens. We propose that ETS factors cause prostate-specific transformation by altering the AR cistrome, priming the prostate epithelium to respond to aberrant upstream signals such as PTEN loss.

E26 transforming sequence-related gene (ERG) is a transcription factor involved in normal hematopoiesis and is dysregulated in leukemia. ERG mRNA overexpression was associated with poor prognosis in a subset of patients with T-cell acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML). Herein, a genome-wide screen of ERG target genes was conducted by chromatin immunoprecipitation-on-chip (ChIP-chip) in Jurkat cells. In this screen, 342 significant annotated genes were derived from this global approach. Notably, ERG-enriched targets included WNT signaling genes: WNT11 , WNT2 , WNT9A , CCND1 and FZD7 . Furthermore, chromatin immunoprecipitation (ChIP) of normal and primary leukemia bone marrow material also confirmed WNT11 as a target of ERG in six of seven patient samples. A larger sampling of patient diagnostic material revealed that ERG and WNT11 mRNA were co-expressed in 80% of AML ( n =30) and 40% in T-ALL ( n =30) bone marrow samples. Small interfering RNA (siRNA)-mediated knockdown of ERG confirmed downregulation of WNT11 transcripts. Conversely, in a tet-on ERG -inducible assay, WNT11 transcripts were co-stimulated. A WNT pathway agonist, 6-bromoindirubin-3-oxime (BIO), was used to determine the effect of cell growth on the ERG -inducible cells. The addition of BIO resulted in an ERG -dependent proliferative growth advantage over ERG -uninduced cells. Finally, ERG induction prompted morphological transformation whereby round unpolarized K562 cells developed elongated protrusions and became polarized. This morphological transformation could effectively be inhibited with BIO and with siRNA knockdown of WNT11 . In conclusion, ERG transcriptional networks in leukemia converge on WNT signaling targets. Specifically, WNT11 emerged as a direct target of ERG. Potent ERG induction promoted morphological transformation through WNT11 signals. The findings in this study unravel new ERG-directed molecular signals that may contribute to the resistance of current therapies in acute leukemia patients with poor prognosis characterized by high ERG mRNA expression.