Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA190034 | ENA |
REPOSITORIES: ENA
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Project description:MYCN and HDAC2 jointly repress the transcription of tumor suppressive micro RNA miR-183 in neuroblastoma. Enforced miR-183 expression induces neuroblastoma cell death and inhibits anchorage-independent colony formation and subcutaneous xenograft growth in mice. We here aimed to unravel the miR-183 signaling network and elucidated the role of MYCN mediated transcriptional activation of members of the minichromosome maintenance (MCM) family protein family involving miR-183 . The hexamer protein complex formed by MCM proteins is involved in the initiation and elongation of eukaryotic genome replication, thereby contributing to genomic integrity. Analysis of miR-183 versus negative control transfected neuroblastoma cells identified 85 differentially expressed proteins in a label-free mass spectrometric approach. Six members of the MCM family were found to be lower expressed upon enforced miR-183 expression, and subsequent annotation category enrichment analysis revealed a 14-fold enrichment in the protein module category “MCM”. Down-regulation was confirmed by western blot analysis. MicroRNA target prediction software studies revealed that miR-183 was predicted to directly target several MCMs.
2016-06-01 | PXD003596 | Pride
Project description:MYCN is a master regulator controlling many processes necessary for tumor cell survival. Here, we unravel a microRNA network that causes tumor suppressive effects in MYCN-amplified neuroblastoma cells. In profiling studies, histone deacetylase (HDAC) inhibitor treatment most strongly induced miR-183. Enforced miR-183 expression triggered apoptosis, and inhibited anchorage-independent colony formation in vitro and xenograft growth in mice. Furthermore, the mechanism of miR-183 induction was found to contribute to the cell death phenotype induced by HDAC inhibitors. Experiments to identify the HDAC(s) involved in miR-183 transcriptional regulation showed that HDAC2 depletion induced miR-183. HDAC2 overexpression reduced miR-183 levels and counteracted the induction caused by HDAC2 depletion or HDAC inhibitor treatment. MYCN was found to recruit HDAC2 in the same complexes to the miR-183 promoter, and HDAC2 depletion enhanced promoter-associated histone H4 pan-acetylation, suggesting epigenetic changes preceded transcriptional activation. These data reveal miR-183 tumor suppressive properties in neuroblastoma that are jointly repressed by MYCN and HDAC2, and suggest a novel way to bypass MYCN function. BE(2)-C neuroblastoma cells were treated with the pan-HDACi HC-toxin (20 nM) or solvent control (methanol) for 24 h in three replicates, respectively.Total RNA was isolated using miRNeasy Mini Kit (Qiagen) according to the manufacturer's instructions. RNA was eluted in water. The quality of total RNA was checked by gel analysis using the total RNA Nanochip assay on an Agilent 2100 Bioanalyzer.
2013-05-01 | E-GEOD-44538 | biostudies-arrayexpress
Project description:MYCN is a master regulator controlling many processes necessary for tumor cell survival. Here, we unravel a microRNA network that causes tumor suppressive effects in MYCN-amplified neuroblastoma cells. In profiling studies, histone deacetylase (HDAC) inhibitor treatment most strongly induced miR-183. Enforced miR-183 expression triggered apoptosis, and inhibited anchorage-independent colony formation in vitro and xenograft growth in mice. Furthermore, the mechanism of miR-183 induction was found to contribute to the cell death phenotype induced by HDAC inhibitors. Experiments to identify the HDAC(s) involved in miR-183 transcriptional regulation showed that HDAC2 depletion induced miR-183. HDAC2 overexpression reduced miR-183 levels and counteracted the induction caused by HDAC2 depletion or HDAC inhibitor treatment. MYCN was found to recruit HDAC2 in the same complexes to the miR-183 promoter, and HDAC2 depletion enhanced promoter-associated histone H4 pan-acetylation, suggesting epigenetic changes preceded transcriptional activation. These data reveal miR-183 tumor suppressive properties in neuroblastoma that are jointly repressed by MYCN and HDAC2, and suggest a novel way to bypass MYCN function.
2013-05-01 | GSE44538 | GEO
Project description:Neuroblastoma is a pediatric cancer of the sympathetic nervous system. MYCN amplification is a key indicator of poor prognosis for the disease, however, mechanisms by which MYCN promotes neuroblastoma tumorigenesis are not fully understood. In this study, we analyzed global miRNA and mRNA expression profiles of tissues at different stages of tumorigenesis from TH-MYCN transgenic mice, a model of MYCN-driven neuroblastoma. Based on a Bayesian learning network model in which we compared pre-tumor ganglia from TH-MYCN+/+ mice to age-matched wild-type controls, we devised a predicted miRNA-mRNA interaction network. Among the miRNA-mRNA interactions operating during human neuroblastoma tumorigenesis, we identified that miR-204 is a tumor suppressor miRNA that inhibits a subnetwork of oncogenes strongly associated with MYCN-amplified neuroblastoma and poor patient outcome. Accordingly, we found that MYCN was bound to the miR-204 promoter and repressed miR-204 transcription, while in contrast, miR-204 directly bound MYCN mRNA and repressed MYCN expression. In support of a tumor suppressor role, miR-204 overexpression significantly inhibited neuroblastoma cell proliferation in vitro and tumorigenesis in vivo. Together these findings identify novel tumorigenic miRNA gene networks and miR-204 as a tumor suppressor that regulates MYCN expression in neuroblastoma tumorigenesis.
2018-06-01 | GSE100658 | GEO
Project description:p53 inactivation occurs only rarely in neuroblastoma, although miR-34, a transcriptional target of p53, is often deleted in neuroblastoma, suggesting another way in which p53 signaling might be impaired. In this study we show that miR-34 directly targets and downregulates the Polycomb Repressive Complex 2 (PRC2) and its associated histone demethylase, JARID1A, in a p53-dependent manner, 8 samples were transfected with siRNA control or JMJD2B, MYCN, JARID1A into NB1691 cells.
2014-01-01 | E-GEOD-49854 | biostudies-arrayexpress
Project description:ALK mutations occur in 10% of primary neuroblastoma and represent a major target for precision treatment. In combination with MYCN amplification, ALK mutations infer an ultra-high-risk phenotype with very poor prognosis. To anticipate to future precision drugging, a deeper understanding of the molecular consequences of constitutive ALK signaling and its relationship to MYCN activity in this aggressive pediatric tumor, will be essential to understand treatment responses and failure as well as to ensure improved design of drugging combinations. We show that mutant ALK downregulates the HMG-box transcription factor 1 (HBP1) through the PI3K-AKT-FOXO3a signaling axis. Interestingly, we also demonstrate that HBP1 is under control of MYCN, through negative regulation of the miR-17~92 cluster. Moreover, modulation of HBP1 in neuroblastoma negatively affect MYCN activity, including alleviating MYCN/PRC2 controlled gene repression. Combined targeting of PI3K and MYCN signaling induced strong synergistic blocking of tumor growth, thus offering potential for targeted therapeutic interventions.
2019-02-14 | GSE95189 | GEO
Project description:ALK mutations occur in 10% of primary neuroblastoma and represent a major target for precision treatment. In combination with MYCN amplification, ALK mutations infer an ultra-high-risk phenotype with very poor prognosis. To anticipate to future precision drugging, a deeper understanding of the molecular consequences of constitutive ALK signaling and its relationship to MYCN activity in this aggressive pediatric tumor, will be essential to understand treatment responses and failure as well as to ensure improved design of drugging combinations. We show that mutant ALK downregulates the HMG-box transcription factor 1 (HBP1) through the PI3K-AKT-FOXO3a signaling axis. Interestingly, we also demonstrate that HBP1 is under control of MYCN, through negative regulation of the miR-17~92 cluster. Moreover, modulation of HBP1 in neuroblastoma negatively affect MYCN activity, including alleviating MYCN/PRC2 controlled gene repression. Combined targeting of PI3K and MYCN signaling induced strong synergistic blocking of tumor growth, thus offering potential for targeted therapeutic interventions.
2019-02-14 | GSE94811 | GEO
Project description:Our work demonstrated that miR-183 cluster regulates IFN production and signaling We used microarrays to detail the effect of miR-183 cluster on hepatic gene expression during immunostimulation with poly(I:C). Our finding suggests enrichment of pathways involved in IFN production and signaling. Amoung the miR-183 repressed genes, we identifies PPP2CA and TRIM27, which are negative regulators of the innate immune response.
2019-11-04 | GSE139027 | GEO
Project description:MYCN amplification in neuroblastoma leads to aberrant expression of MYCN oncoprotein, which binds active genes promoting transcriptional amplification. Yet how MYCN coordinates transcription elongation to meet productive transcriptional amplification and which elongation machinery represents MYCN-driven vulnerability remain to be identified. We conducted a targeted screen of transcription elongation factors and identified the super elongation complex (SEC) as a unique vulnerability in MYCN-amplified neuroblastomas. MYCN directly binds EAF1 and recruits SEC to enhance processive transcription elongation. Depletion of EAF1 or AFF1/AFF4, another core subunit of SEC, leads to a global reduction in transcription elongation and elicits selective apoptosis of MYCN-amplified neuroblastoma cells. A combination screen reveals SEC inhibition synergistically potentiates the therapeutic efficacies of FDA-approved BCL2 antagonist ABT-199, in part due to suppression of MCL1 expression, both in MYCN-amplified neuroblastoma cells and in patient-derived xenografts. These findings identify disruption of the MYCN-SEC regulatory axis as a promising therapeutic strategy in neuroblastoma.
2023-05-10 | PXD039332 | Pride