ERG overexpression

HDAC7 promotes the growth of human and mouse AEL cells both in vitro and in vivo through its non-enzymatic functions. Our study provides experimental evidence that TP53 deficiency and ERG overexpression are necessary and sufficient for the development of AEL and highlights HDAC7 as a promising therapeutic target for this disease.

These results suggested that a certain threshold level of LDB1 expression enables FLI1 to block erythroid differentiation. Overall, FLI1 controlled the commitment of MEP to either erythroid or megakaryocytic lineage through an intricate regulation of GATA1/GATA2, LDB1 and ERG, exposing multiple targets for cell fate commitment and therapeutic intervention.

Statistical analysis was done with Statistica and R software. When analyzing the expression of miRNAs some differences could be seen, but after correction for multiple comparisons was applied, these were found to be non- significant.

Using a large, diverse, national cohort, we observed considerable variations in gene expression profiles across groups by race, age, Gleason grade group, and geographic region that can address the genomic underpinnings of sociodemographic and geographic variation in prostate cancer outcomes.

Overexpression of FABP4 could effectively block the inhibition role of NKX2-1-AS1 silencing in lymphangiogenesis in H441 and H661 cells. This study provided evidence that NKX2-1-AS1 regulated FABP4 transcription by binding to ERG to facilitate the proliferation and migration of LUAD cells and tube formation of HLECs, thus participating in lymphangiogenesis.

In conclusion, our results indicate that UF and MF PCa have relevant and consistent molecular differences. The analysis of an immunohistochemical panel, composed by PTEN, SPOP, SLC45A3, ETV1 and ERG, could be useful to predict outcome in MF cases.

In mice, prostate-specific Snd1 deletion reduces cancer growth and tumor burden in a prostate cancer model (PB-Cre/Pten/ERG mice), Moreover, we find a significant overlap between prostate transcriptional signatures of ERG and SND1. These findings highlight SND1's crucial role in prostate tumorigenesis, suggesting SND1 as a potential therapeutic target in prostate cancer.

Like the well-known disease genes GATA2 and RUNX1, ERG is also a member of the transcription factor heptad involved in HSC maintenance and differentiation. ERG adds to a growing list of genes whose unregulated expression contributes to HM and other cancers.Identification of causal germline ERG variants like those outlined in this study, has direct clinical implications for patient and family management including diagnosis, counselling, surveillance and treatment strategies such as selection of bone marrow transplant donors and potential for targeted therapies including gene and cell therapy.

This study indicates that miR-4482 and -3912 can suppress the ERG expression and its target genes, thereby, halt prostate cancer progression. These miRNAs may be employed as a potential therapeutic target for the miRNA-based therapy against prostate cancer.

Although, at some degree, ERG expression seems to be associated with the morphological features of prostate cancer, different studies reported controversial results. However, expression of PTEN is more clearly associated with the pathology and clinical course of the disease. More research is required to elucidate the role of these molecules in the molecular pathology of prostate cancer, as well as their potential use as therapeutic targets.

Nonetheless, our findings corroborate tissue-based molecular data demonstrating ERG is less overexpressed in AA men’s tumors. These data underscore the importance of considering race in the development of PCa biomarkers.

Our findings indicate that the aberrant overexpression of ERG maintains HSPCs in an undifferentiated state and promotes AML development. We suggest that the interaction between ERG and the NCoR-HDAC3 complex has an important role in the leukemogenic process, and that HDAC3 inhibition could be beneficial in AML characterized by high ERG expression.

Importantly, there was a significant increase in immune cell infiltrations, which increased with the stage of tumorigenesis, in the TMPRSS2-ERG fusion-positive tumors relative to fusion negative tumors. Together, these findings are both novel and highly significant in establishing a working preclinical model for evaluating the efficacy of interventions during different stages of tumorigenesis in TMPRSS2-ERG fusion-driven PCa.

ERG has also been implicated in the epithelial-mesenchymal transition (EMT) in PCa cells, which increases the ability of cancer cells to metastasize. In vivo, research has demonstrated that higher levels of ERG expression are involved with nuclear pleomorphism that prompts hyperplasia and the loss of cell polarity.

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.

In prostate cancer, gene fusion and overexpression of ETS factors ERG, FLI1, ETV1, ETV4 and ETV5 have been found in half of prostate cancer patients in Caucasian men and define the largest genetic subtype of prostate cancer. This review summarizes the data on the discovery, modeling, molecular taxonomy, lineage plasticity and therapeutic targeting of ETS family members in prostate cancer.

DNA-methylation might aid in opening of adjacent chromatin on ERG to possibly facilitate SE enrichment and over-expression the gene. Future studies will investigate targeted alterations of DNA-methylation on the gene to test the impact on ERG expression and leukemic growth.

P20-23 PDOs were derived from a transurethral prostate resection obtained from a patient with metastatic castration-resistant PCa, previously treated with goserelin, docetaxel, and enzalutamide. We have successfully generated two novel PDOX models, which highly resemble the original patients’ tumor and can be further cultured as organoids. These models are representative of relevant clinical and molecular subtypes of advanced PCa, providing further opportunities for translational studies.

We present results on the expression of each protein biomarker in the context of patient race and their association with clinico-pathologic features, together with concurrence or mutual exclusiveness for each event. These results support the application of ETS monoclonal antibodies in IHC assays to detect prostate cancer tumor heterogeneity and to identify subsets of prostate cancer.

Here we report the new and more potent ERG inhibitor ERGi-USU-6 developed by structure-activity studies from the parental ERGi-USU. We have developed an improved procedure for the synthesis of ERGi-USU-6 and identified a salt formulation that further improves its activity in biological assays for selective targeting of ERG harboring prostate cancer cells.

They also exhibited increased activity of an ERG network with the overexpression of upstream regulators CBFA2T3 and GATA, and downstream targets like VWF and ZBTB16. Overall, we show that ETS fusions are uniformly high risk and share dysregulated cell adhesion (EDIL3) and transcriptional networks for ERG, HPGD, and PTP4A3, which provide opportunities for further research into the metabolome and therapeutics (BETi) in these fusions.

This study indicates that the overexpression of ERG co-option has a unique cis-regulatory structure in T2E positive thyroid tumors, which induces drug dependence on CBF-1/RBP-Jκ signal. Our study solved the genetic and epigenetic variation of T2E in metastatic thyroid cancer for the first time. It is worth noting that further functional and clinical validation is needed as our study is a bioinformatics analysis.

Here, we explore whether TMPRSS2-ERG affects outcomes of patients (pts) with metastatic hormone sensitive PC (mHSPC). We conducted a multicenter, retrospective, biomarker study that included 218 mHSPC pts: 125 received androgen deprivation (ADT) + Docetaxel (DX) and 93 received ADT only... TMPRSS2-ERG expression associates with longer time to CRPC and OS in mHSPC treated with ADT only, but not in those treated with ADT+DX. Further characterization of TMRPSS2-ERG in the context of different treatments for mHSPC is warranted to elucidate its role as a predictive biomarker and potentially assist treatment selection.

However, these effects of XPD overexpression were abrogated by GW9662. Collectively, XPD suppresses proliferation and promotes apoptosis of HepG2 cells by downregulating ERG expression via activation of the PPARγ pathway.

Importantly, the clinical and pathologic features associated with distinct late events at radical prostatectomy were strikingly different; PTEN deletions were associated with increased locoregional stage, while CHD1 deletions were only associated with increased grade, despite equivalent metastatic potential.CONCLUSIONThese findings suggest a paradigm in which specific subtypes of PCa follow distinct pathways of progression, at both the molecular and clinical levels. Therefore, the interpretation of common clinical parameters such as locoregional tumor stage may be influenced by the underlying tumor lineage, and potentially influence management decisions.FUNDINGProstate Cancer Foundation, National Cancer Institute, Urology Care Foundation, Damon Runyon Cancer Research Foundation, US Department of Defense, and the AIRC Foundation.

Finally, out of 9 metastasis samples, we generated a novel organoid model derived from a hormone-naive lung metastasis, which displays alterations in the PI3K/Akt and Wnt/ß-catenin pathways and responds to androgen deprivation. Taken together, our comprehensive study explores determinants of outcome and highlights the opportunities and challenges associated with the establishment of stable tumor organoid lines derived from PCa patients.

Arsenic trioxide decreased the expression level of ERG, further promoting cell differentiation. Furthermore, the mutation of SUMO sites in ERG inhibited its ability to promote the proliferation and inhibit the differentiation of leukemia cells. Our results demonstrated the crucial role of ERG SUMOylation in the development of AML, providing powerful targeted therapeutic strategies for the clinical treatment of AML.

The TLR4 inhibitor, TAK-242, attenuated ERG-mediated migration, clonogenic survival, target gene activation and tumor growth. Together these data indicate a mechanistic basis for inhibition of TLR4 signaling as a treatment for ERG-positive prostate cancer.

Luciferase promoter assays using the wildtype and mutated ERG binding site within the CD24 promoter showed ERG-dependent activation. Collectively, our results suggest that promoter DNA methylation of the CD24 gene and T2E fusion status are factors involved in the upregulation of CD24 in patients with PCa.

ERG IHC of HGPIN foci should be performed in needle biopsies without PCa, as most of the ERG+ HGPIN cases seem to be associated to a concomitant PCa. ISCIII/FIS-FEDER grant PI15/00452