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MYCN and HDAC2 cooperate to repress miR-183 signaling in neuroblastoma.

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE44538 | GEO | 2013/05/01

SECONDARY ACCESSION(S): PRJNA190034

REPOSITORIES: GEO

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MYCN and HDAC2 cooperate to repress miR-183 signaling in neuroblastoma.

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

Inhibitory effect of miR-183 on MCM family members

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

Homo sapiens

Project description:MYCN and HDAC2 cooperate to repress miR-183 signaling in neuroblastoma.

| PRJNA190034 | ENA

miR-204 blocks MYCN expression and is a novel a tumor suppressor in neuroblastoma tumorigenesis

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

Gene expression profiling of miR-183/96 knock out mouse cochlea

Project description:Transcriptome analysis of P16 cochlea from wild type and miR-183/96 Knock out mice Gene expression analysis of miR-183/96 KO cochlea revealed a set of hair cell-relevant differentially expressed genes that could adversely impact hair cell physiology and contribute to the observed phenotype.

2018-05-01 | GSE106599 | GEO

GRHL1 acts as a tumor suppressor in neuroblastoma and is negatively regulated by MYCN and HDAC3

Project description:Neuroblastoma is an embryonic solid tumor of neural crest origin and accounts for 11% of all cancer-related deaths in children. Novel therapeutic strategies are therefore urgently required. MYCN oncogene amplification, which occurs in 20% of neuroblastomas, is a hallmark of high risk. Here we aimed to exploit molecular mechanisms that can be pharmacologically addressed with epigenetically modifying drugs, such as histone deacetylase (HDAC) inhibitors. GRHL1, a gene critical for Drosophila neural development, belonged to the genes most strongly responding to HDAC inhibitor treatment of neuroblastoma cells in a genome- wide screen. An increase in the histone H4 pan-acetylation associated with its promoter preceded transcriptional activation. Physically adjacent, HDAC3 and MYCN co-localized to the GRHL1 promoter and repressed its transcription. High-level GRHL1 expression in primary neuroblastomas correlated on transcriptional and translational levels with favorable patient survival and established clinical and molecular markers for favorable tumor biology, including lack of MYCN amplification. Enforced GRHL1 expression in MYCN-amplified neuroblastoma cells with low endogenous GRHL1 levels abrogated anchorage-independent colony formation, inhibited proliferation and retarded xenograft growth in mice. GRHL1 regulated 170 genes genome-wide, and most were involved in pathways regulated during neuroblastomagenesis, including nervous system development, proliferation, cell-cell adhesion, cell spreading and cellular differentiation. In summary, the data presented here indicate a significant role of HDAC3 in the MYCN-mediated repression of GRHL1 and suggest drugs that block HDAC3 activity and suppress MYCN expression as promising candidates for novel treatment strategies of high-risk neuroblastoma. Twelve samples were analyzed. Each 2 replicated of paired empty vector control and GRHL1 forced expression at 3 different time points.

2014-05-22 | E-GEOD-47407 | biostudies-arrayexpress

Transcriptomics analysis of cells transfected with miR-183 cluster mimics and immunostimulated with poly(I:C)

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

The transcriptional co-repressor Runx1t1 is essential for MYCN-driven neuroblastoma tumorigenesis

Project description:Changes in epigenetic regulation are believed to be a major contributing factor to neuroblastoma development. Using a large-scale in vivo mutagenesis screen in Th-MYCN transgenic mice, we identified a single point mutation in the transcriptional corepressor Runx1t1, that can block N-myc-driven neuroblastoma tumorigenesis. The loss of function mutation disrupts a highly conserved zinc finger domain (NHR4) within Runx1t1. Crossing an independent Runx1t1 knockout model with Th-MYCN mice, demonstrated that Runx1t1 haploinsufficiency is enough to prevent neuroblastoma development and reverse ganglia hyperplasia. Silencing RUNX1T1 in human neuroblastoma cells resulted in decreased colony formation in vitro, and significant inhibition of tumor growth in vivo. Our results show that RUNX1T1 forms part of a transcriptional LSD1-CoREST3-HDAC repressive complex that regulates the epigenomic landscape and chromatin accessibility, to control neuron-specific pathway genes and maintain an undifferentiated state. Runx1t1 thus represents an entirely novel and highly promising target not previously described in neuroblastoma.

2024-08-10 | PXD050375 | Pride

Expression data from the RWPE-1 prostate epithelial cell line overexpressing the miR-183 family cluster

Project description:The full genomic miR-183 cluster (4.8kb) was cloned into lentiviral vector CD511B-1 with polycistronic GFP. RWPE-1 were transduced with a lentivirus from this vector (RWPE-1 183FC), or a CD511B-1 scrambled control with polycistronic GFP (RWPE-1 control). RWPE-1 were FACS sorted by GFP expression and expanded in culture. In RWPE-1 183FC, the miR-183 family members, miR-182, miR-96, and miR-183 were confirmed to be over-expressed at physioloically relevent levels, similar to the increased expression observed in prostate cancer epithelium.

2017-05-23 | GSE99134 | GEO

Human MDA-MB-231 breast cancer cells overexpressing miR-183-5p and its isomiRs

Project description:Overexpression of miR-183-5p|+2, but not of the other two isomiRs |0 and |+1, was observed to reduce cell cycle and cell proliferation in different triple-negative breast cancer cell lines. Therefore, we hypothesized that the |+2 isoform has targets distinct from the other two isoforms. To test this hypothesis, we overexpressed separately the three different isoforms or negative controls (siAllstar or mimic-Cltr) and performed Mass Spectrometry to identify differentially regulated proteins. Interestingly, a gene set enrichment analysis of the changes in protein expression revealed significant downregulation of transcriptional targets of E2F specifically in cells transfected with the |+2 isoform prompting us to validate the predicted isomiR specific target E2F1. Subsequently, we could show that direct targeting of E2F1 by miR-183-5p|+2 is responsible for the impact of the isomiR on cell cycle and proliferation.

2022-05-26 | PXD026763 | Pride

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