H3K27ac ChIP-seq in TMPRSS2:ERG positive and negative prostate cancer tissue samples
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PROVIDER: EGAS00001002496 | EGA |
REPOSITORIES: EGA
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Project description:Structural rearrangements leading to the TMPRSS2:ERG (T2E) fusion typify ~50% of prostate tumors and result in overexpression of the ERG transcription factor. Using T2E and non-T2E primary prostate tumors, we assessed the impact of ERG overexpression on chromatin by integrating ChIP-seq against H3K27ac, a chromatin modification found at active cis-regulatory elements, with paired genomic and expression data. We show that T2E tumors have a consistent and distinct cis-regulatory landscape to non-T2E tumors which drives their unique transcriptional profile. The T2E-specific cis-regulatory landscape is driven by ERG-mediated co-option of prostate master transcription factors HOXB13 and FOXA1 and is typified by Cluster Of Regulatory Elements (COREs) including one spreading into the ERG locus of the structurally rearranged allele. This gives rise to a cis-regulatory element within the rearranged ERG gene that contributes to ERG overexpression. The unique cis-regulatory landscape in T2E primary prostate tumors also reveals the activation of the NOTCH signalling pathway. Accordingly, chemical NOTCH pathway inhibition limited the invasive nature of T2E prostate cancer cells, revealing an actionable vulnerability against T2E prostate tumors. Taken together, our work delineates the role of ERG over-expression in co-opting master transcription factors to deploy a unique cis-regulatory landscape inducing a dependency on NOTCH signaling in T2E prostate tumors.
2017-07-25 | GSE96652 | GEO
Project description:Common epithelial cancers are believed to become more aggressive through the accumulation of multiple independent molecular events that lead to the deregulation of cell signaling. However, the discovery that the majority of prostate cancers harbor gene fusions of the 5'-untranslated region of androgen regulated TMPRSS2 promoter with ETS transcription factor family members has brought this paradigm into question1,2. TMPRSS2-ERG gene fusion is the most common molecular sub-type of prostate cancer. Recent work suggests that the TMPRSS2-ERG fusion is associated with a more aggressive clinical phenotype3. In the most advanced castration resistant prostate cancers where the androgen receptor has been inactivated, the TMPRSS2-ERG fusion remains functionally active. Here we show compelling clinical and gene expression data supporting the existence of a TMPRSS2-ERG fusion prostate cancer subclass. Using expression array profiling on 455 primary prostate tumors, we identified an 87 gene expression signature, distinguishing TMPRSS2-ERG fusion prostate cancer as a discrete molecular entity. Computational analysis suggested that this fusion signature was associated with estrogen receptor signaling. Functional studies demonstrated regulation of the TMPRSS2-ERG fusion transcript by estrogenic compounds. These data identify a previously unrecognized mechanism for regulation of the TMPRSS2-ERG, even in the absence of a functional androgen receptor, and thus may have broader implications in the treatment of prostate cancer. Keywords: Prostate cancer, Expression array, Illumina, gene fusion, TMPRSS2, ERG, Signatures, Estrogen Test Cohort: 388 cases from the population based Swedish-Watchful Waiting cohort. The cohort consists of men with localized prostate cancer (clinical stage T1-T2, Mx, N0); Validation cohort: The PhysiciansM-bM-^@M-^Y Health Study (PHS) cohort included 116 US men diagnosed with incidental prostate cancer between 1983 and 2003; 455 cases were annotated for TMPRSS2-ERG fusion. Test Set: GSM208029 ... GSM208392 Validation Set: GSM208404 ... GSM208512
2008-05-27 | E-GEOD-8402 | biostudies-arrayexpress
Project description:Common epithelial cancers are believed to become more aggressive through the accumulation of multiple independent molecular events that lead to the deregulation of cell signaling. However, the discovery that the majority of prostate cancers harbor gene fusions of the 5'-untranslated region of androgen regulated TMPRSS2 promoter with ETS transcription factor family members has brought this paradigm into question1,2. TMPRSS2-ERG gene fusion is the most common molecular sub-type of prostate cancer. Recent work suggests that the TMPRSS2-ERG fusion is associated with a more aggressive clinical phenotype3. In the most advanced castration resistant prostate cancers where the androgen receptor has been inactivated, the TMPRSS2-ERG fusion remains functionally active. Here we show compelling clinical and gene expression data supporting the existence of a TMPRSS2-ERG fusion prostate cancer subclass. Using expression array profiling on 455 primary prostate tumors, we identified an 87 gene expression signature, distinguishing TMPRSS2-ERG fusion prostate cancer as a discrete molecular entity. Computational analysis suggested that this fusion signature was associated with estrogen receptor signaling. Functional studies demonstrated regulation of the TMPRSS2-ERG fusion transcript by estrogenic compounds. These data identify a previously unrecognized mechanism for regulation of the TMPRSS2-ERG, even in the absence of a functional androgen receptor, and thus may have broader implications in the treatment of prostate cancer. Keywords: Prostate cancer, Expression array, Illumina, gene fusion, TMPRSS2, ERG, Signatures, Estrogen
2008-05-28 | GSE8402 | GEO
Project description:ERG is a transcriptional factor, which is recombined with promoter of TMPRSS2 and prominently overexpressed in half of human prostate cancers. The mechanisms of ERG-mediated oncogenesis are not completely understood. We performed an unbiased Mass Spectrometry screen for ERG-binding proteins and found that ERG binds to MTDH/SND1 protein complex in prostate cancer cells. We determined that ERG binds to the SND1/MTDH protein complex via SND1 and this interaction plays a critical role in ERG-mediated cancer.
2023-03-22 | PXD036882 | Pride
Project description:Chromosomal translocations juxtaposing the androgen-responsive TMPRSS2 promoter with the ETS-family transcription factor ERG result in aberrant ERG up-regulation in approximately 50% of prostate cancers. Studies to date have demonstrated important roles of ERG in inducing oncogenic properties of prostate cancer. Its molecular mechanisms of action, however, are yet to be fully understood. To address these questions, we generated engineered LNCaP cells with ERG overexpression followed by LEF1 knockdown as well as control cell lines. To further investigate the role of LEF1 in ERG fusion positive samples, we also knockdown ERG in VCaP cell line. We performed microarray analysis on LNCaP cells with ERG overexpression followed by LEF1 knockdown using siRNA. We also knockdown endogenous ERG in fusion-positive cell line VCaP.
2013-05-29 | E-GEOD-47423 | biostudies-arrayexpress
Project description:Antineoplastic effects of siRNA against TMPRSS2-ERG junction oncogene in prostate cancer: from molecular and cellular studies to preclinical investigations. Background of the study.:TMPRSS2-ERG junction oncogene is present in more than 50% of patients with prostate cancer, and its expression is frequently associated with poor prognosis. We knockdown by siRNA the two TMPRSS2-ERG fusion variants (III and IV) most frequently identified in patients’ biopsies and found an inhibition of TMPRSS2-ERG of above 70% in human prostate cancer VCaP cell line expressing TMPRSS2-ERG junction oncogene. To point out genes regulated after TMPRSS2-ERG oncogene silencing, microarray analysis was performed.. Materiel and Methods. Human prostate cancer VCaP cell line expressing TMPRSS2-ERG oncogene (ATCC® CRL-2876™ Manassas, USA) was grown in Dulbecco's Modified Eagle Medium (DMEM) (Invitrogen, Cergy-Pontoise, France) supplemented with 10% fetal bovine serum (FBS), 100 units/ml penicillin and 100 μg/ml streptomycin (Invitrogen). Cells were incubated at 37°C in a humidified atmosphere containing 5% CO2. Transfection was carried out using Lipofectamine RNAiMAX transfecting agent (Invitrogen) according to manufacturer's instructions. Briefly, 8×105 VCaP cells were seeded in six-well plates in DMEM supplemented with 10% FCS, penicillin (100U/ml) and streptomycin (10µg/ml) and transfected with 50 nM siRNA TMPRSS2-ERG III, siRNA TMPRSS2-ERG IV and siRNA Control and 6 μL Lipofectamine® RNAiMAX. Cells were incubated with siRNA for 48h. At the end of the treatments, total RNAs of untreated cells (NT) and transfected cells were extracted using RNeasy mini-kit (Quiagen, Courtaboeuf, France). Three independent experiments were performed. Results. Microarray analysis confirmed ERG inhibition by both siRNA TMPRSS2-ERG III and IV and revealed a common down-regulated gene, ADRA2A, involved in cell proliferation and migration. Experiments are performed with Agilent Whole Genome 8x60K (028004) microarray. In triplicate with a non treated control cells, a control with ascramble siRNA, a siRNA TMPRSS2-ERG III, a siRNA TMPRSS2 IV.
2015-01-09 | E-MTAB-2838 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the following subset Series: GSE28948: TMPRSS2-ERG, HDACs and EZH2 are involved in an AR-centric transcriptional circuitry that calibrates androgenic response for prostate cancer progression (gene expression data) GSE28950: TMPRSS2-ERG, HDACs and EZH2 are involved in an AR-centric transcriptional circuitry that calibrates androgenic response for prostate cancer progression (ChIP-Seq data) GSE35540: TMPRSS2-ERG, HDACs and EZH2 are involved in an AR centric transcriptional circuitry that calibrates androgenic response for prostate cancer progression (gene expression after ERG KD) Refer to individual Series
2012-04-26 | E-GEOD-28951 | biostudies-arrayexpress
Project description:Androgen receptor (AR) is a transcription factor that plays a central role in the growth and development of the normal prostate and its malignant transformation. More recently, a majority of prostate cancers have been shown to harbor recurrent gene fusions of the androgen-regulated gene, TMPRSS2, to the oncogenic ETS transcription factor ERG. Here we employed chromatin immunoprecipitation coupled to massively parallel sequencing (ChIP-Seq) to explore the genome-wide localization of these transcription factors in human prostate cancer cell lines as well as tissues. Unexpectedly, transcriptional networks emanating from AR and ERG were found to be highly overlapping. Furthermore, AR was found to regulate known 5’ fusion partners in prostate cancer including TMPRSS2, as well as negatively regulating its own expression. While induced by androgen through fusion to TMPRSS2, ERG itself was shown to inhibit AR expression and positively regulate the genomic locus of wild-type ERG, thus revealing multiple levels of molecular cross-talk between AR and ERG. Importantly, androgen-sensitive prostate cancer cells in which ERG is overexpressed are able to proliferate and invade in the absence of androgen. Thus, we dissected the intertwined genomic landscape of two master transcriptional regulators of prostate cancer and suggest a role for ERG in maintaining transcriptional networks necessary for androgen-independent prostate cancer growth. These studies may suggest that future therapies against prostate cancer should target both AR and ERG, rather than AR alone, in order to achieve maximum effectiveness.
2010-05-18 | GSE14092 | GEO
Project description:Androgen receptor (AR) is a transcription factor that plays a central role in the growth and development of the normal prostate and its malignant transformation. More recently, a majority of prostate cancers have been shown to harbor recurrent gene fusions of the androgen-regulated gene, TMPRSS2, to the oncogenic ETS transcription factor ERG. Here we employed chromatin immunoprecipitation coupled to massively parallel sequencing (ChIP-Seq) to explore the genome-wide localization of these transcription factors in human prostate cancer cell lines as well as tissues. Unexpectedly, transcriptional networks emanating from AR and ERG were found to be highly overlapping. Furthermore, AR was found to regulate known 5’ fusion partners in prostate cancer including TMPRSS2, as well as negatively regulating its own expression. While induced by androgen through fusion to TMPRSS2, ERG itself was shown to inhibit AR expression and positively regulate the genomic locus of wild-type ERG, thus revealing multiple levels of molecular cross-talk between AR and ERG. Importantly, androgen-sensitive prostate cancer cells in which ERG is overexpressed are able to proliferate and invade in the absence of androgen. Thus, we dissected the intertwined genomic landscape of two master transcriptional regulators of prostate cancer and suggest a role for ERG in maintaining transcriptional networks necessary for androgen-independent prostate cancer growth. These studies may suggest that future therapies against prostate cancer should target both AR and ERG, rather than AR alone, in order to achieve maximum effectiveness. Keywords: Genetic modification
2010-05-18 | GSE14028 | GEO
Project description:Here, we developed immunoprecipitation-mass spectrometry assays for the measurement of a low-abundance T1E4 TMPRSS2-ERG fusion protein, its isoforms and its interactome in VCaP prostate cancer cells.
2021-03-29 | PXD021236 | Pride