MiRNA expression profiling of Prostate Epithelial Cells (PrEc) with ESE3 knock-down
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE59934 | GEO | 2017/12/31
SECONDARY ACCESSION(S): PRJNA257104
REPOSITORIES: GEO
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Project description:To identify genomic regions which display concordant gene expression in prostate cancer, we performed expression profiling of normal prostate epithelial cells (PrEC) and the prostate cancer cell line LNCaP. These expression arrays were integrated ChIP-on-chip studies of active and repressive epigenetic marks in same cells to discover and characterise regions of Long Range Epigenetic Silencing (LRES) in prostate cancer.
2010-01-04 | GSE19725 | GEO
Project description:To identify genomic regions which display concordant epigenetics alterations in prostate cancer, we performed MeDIP and ChIP-on-chip profiling of normal prostate epithelial cells (PrEC) and the prostate cancer cell line LNCaP. These promoter arrays were integrated with expression arrays of the same cells to discover and characterise regions of Long Range Epigenetic Silencing (LRES) in prostate cancer.
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Project description:MicroRNAs (miRNAs) play important roles in cell differentiation and self-renewal controlling post-transcriptional processing of mRNAs and attenuating production of the encoded proteins. Here, we unveil a novel oncogenic pathway leading to activation of STAT3 signaling through miRNA-mediated silencing of the E3 ubiquitin ligase COP1. miRNA profiling showed that miR-424 was upregulated in prostate cancer compared to normal prostate and specifically associated with reduced level of the ETS factor ESE3/EHF in an aggressive subgroup of tumors. MiR-424 was significantly elevated also in other epithelial cancers and amplified in 1-3% of various cancers. In normal prostate epithelial cells miR-424 was repressed by ESE3/EHF and when upregulated promoted oncogenic and cancer stem cell (CSC) properties. Conversely, ablation of miR-424 in metastatic prostate cancer cells reduced CSC self-renewal and prevented in vivo tumour initiation and metastatic spread. miR-424 targeted the 3' UTR of COP1 mRNA and reduced COP1 protein level. COP1 induced STAT3 ubiquitylation and degradation by the ubiquitin-proteasome system (UPS). Therefore, reduced levels of COP1 in prostate cancer cells, resulted in accumulation and increased STAT3 signaling. COP1 knockdown and over-expression phenocopied the effects of miR-424 deregulation on oncogenic phenotypes and STAT3 signalling, while STAT3 knockdown prevented the transforming effects of miR-424. Consistently, expression of EHF/ESE3 and RFWD2/COP1 were highly correlated in human prostate cancers and other epithelial tumors. Furthermore, miR-424 induced genes were enriched of STAT3 targets, converged with those induced by COP1 loss in mouse embryos and were associated with adverse prognosis in prostate and other epithelial cancers. In primary prostate tumours, low COP1 and high STAT3 protein level were also significantly associated and predictive of biochemical relapse. Collectively, this study reveals a novel miRNA-activated oncogenic axis in prostate cancer. Targeting miR-424 or miR-424 dependent pathways may represent a unique approach to attack a key node in tumorigenesis.
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Project description:ETS transcription factors have recently emerged as important elements in the pathogenesis of prostate cancer (PCa). ETS gene rearrangements leading to over-expression of ETS factors, like ERG, ETV1 and ETV4, are found in about 50% of prostate tumors. While the oncogenic potential of translocated ETS has been demonstrated in several contexts, the impact of endogenously expressed ETS factors on prostate tumorigenesis has been largely overlooked. Here we show that the epithelial-specific ETS factor ESE3, which is normally expressed in basal prostate epithelial (PrE) cells and frequently down-regulated in prostate tumors, serves as gatekeeper to maintain cell differentiation and its down-regulation leads to the acquisition of mesenchymal, stem cell (SC) and tumorigenic properties. ESE3 exerts this function by regulating critical genes involved in the epithelial to mesenchymal transition (EMT) and cell “stemness” and maintaining the equilibrium between cell differentiation and proliferation. Loss of ESE3 may be an important step in prostate tumorigenesis. Keywords: prostate epithelial cells, prostate cancer, gene expression profiling, ETS genes, EMT, cancer stem cells
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Project description:Effects of sulforaphane and 3,3’-diindolylmethane on genome-wide promoter methylation in normal prostate epithelial cells and prostate cancer cells This study was undertaken to determine the genome-wide effects of sulforaphane (SFN) and 3,3’-diindolylmethane (DIM) on promoter methylation in normal prostate epithelial cells and prostate cancer cells. Nimblegen Human DNA Methylation 3x720K CpG Island Plus RefSeq Promoter Array was used in this study. We hypothesize that both SFN and DIM are effective dietary modulators of DNA methylation due to their inhibitory effects on DNMT expression, and that SFN and DIM can differentially affect the promoter methylation profiles in normal and cancerous prostate epithelial cells. Normal prostate epithelial cells (PrEC), androgen-dependent prostate cancer epithelial cells (LnCAP) and androgen-independent prostate cancer epithelial cells (PC3) were treated with vehicle control, 15uM SFN, or 15uM DIM for 48h in triplicates
2014-01-01 | E-GEOD-47017 | biostudies-arrayexpress
Project description:To validate a panel of selected genes expression in prostate cancer, we performed expression profiling of normal prostate epithelial cells (PrEC) and the prostate cancer cell line LNCaP using qPCR.
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Project description:Deregulated expression of ETS transcription factors with oncogenic and tumor suppressor function occurs frequently in prostate cancer leading to profound alterations of the cancer transcriptome. By integrating genomic and functional studies we identified key targets of the aberrantly expressed ETS factors, ERG and ESE3. Altered expression of ETS factors led to the induction of the polycomb group protein EZH2 and silencing of the tumor suppressor Nkx3.1. Nkx3.1 was controlled by ERG and ESE3 both directly via binding to ETS binding sites in the gene promoter and indirectly via EZH2-induced histone H3K27 methylation. This may represent a general mechanism linking aberrantly expressed ETS with deregulation of epigenetic pathways and global reprogramming of the prostate epithelial cell transcriptome in prostate tumorigenesis. Keywords: prostate cancer, gene expression profiling, ETS genes
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Project description:Deregulated expression of ETS transcription factors with oncogenic and tumor suppressor function occurs frequently in prostate cancer leading to profound alterations of the cancer transcriptome. By integrating genomic and functional studies we identified key targets of the aberrantly expressed ETS factors, ERG and ESE3. Altered expression of ETS factors led to the induction of the polycomb group protein EZH2 and silencing of the tumor suppressor Nkx3.1. Nkx3.1 was controlled by ERG and ESE3 both directly via binding to ETS binding sites in the gene promoter and indirectly via EZH2-induced histone H3K27 methylation. This may represent a general mechanism linking aberrantly expressed ETS with deregulation of epigenetic pathways and global reprogramming of the prostate epithelial cell transcriptome in prostate tumorigenesis. Keywords: prostate cancer, gene expression profiling, ETS genes In this study we show that deregulated expression of ETS factors with opposite functions is highly frequent in prostate cancer. Our study uncovers a previously unrecognized link between aberrant expression of ETS factors, deregulation of epigenetic pathways and silencing of tumor suppressor genes in prostate cancer and shows that partially distinct transcriptional programs are associated with different ETS gene expression patterns. The presence of distinct prostate cancer subgroups with different biological features may have important clinical implications and suggests that assessment of ETS expression levels might be useful to distinguish tumors with different clinical outcome.
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