Genome-wide mapping of MYCN binding in neuroblastoma cells
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE72640 | GEO | 2016/05/16
SECONDARY ACCESSION(S): PRJNA294529
REPOSITORIES: GEO
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Project description:To identify the MYCN transcription factor binding sites across the genome, we performed chromatin immunoprecipitation followed by sequencing (ChIP-seq) using anti-MYCN and anti-IgG antibodies on a MYCN-amplified NB cell line, SK-N-BE(2)-C. Identification of MYCN binding in neuroblastoma cells.
2016-05-16 | E-GEOD-72640 | biostudies-arrayexpress
Project description:The MYCN locus is amplified in about half of high-risk neuroblastoma tumors. To identify genomic loci occupied by MYCN protein in the MYCN-amplified neuroblastoma cell lines NGP, Kelly and NB-1643, we performed chromatin immunoprecipitation coupled with Next-Generation Sequencing (ChIP-seq) using an anti-MYCN antibody.
2017-08-02 | GSE94782 | GEO
Project description:To evaluate the expression of genes associated with MYCN in NB, 10 tumors with MYCN amplification and 10 with normal MYCN copy number were subjected to oligonucleotide microarray using Agilent oligo microarray chips. Two-condition experiment, MYCN normal vs. MYCN amplified 10 NB patient tissues for each group.
2013-12-17 | E-GEOD-53371 | biostudies-arrayexpress
Project description:Neuroblastoma (NB) is a childhood cancer in which the MYCN amplification is the most acknowledged marker of poor prognosis. MYCN-amplified NB cells showed to rely on both glycolysis and oxidative phosphorylation system (OXPHOS) for energy production . Previously, we revealed that a ketogenic diet (KD) slowed the tumor growth in MYCN NB xenografts, when combined with classical cytotoxic therapy cyclophosphamide (CP). Metformin (MET) is a compound that targets complex I of the OXPHOS system. Therefore, the aim of this study was to elucidate whether MET can enhance the anti-tumorigenic effects of a KD in NB. Our result indicated that MET decreasedcell proliferation andrespiration in NB cells in vitro. The combination of KD, MET and low dose of chemotherapyreduced also the tumor growth and improved survival in NB xenografts. GO enrichment analysis revealed fatty acid ß-oxidation as the most upregulated process resulting from the addition of MET to KD. The differential expression of CPT1A and of its direct regulator ACC might determine an unbalanced redox state and dictate the anti-tumor effect of the combination therapy in MYCN-amplified xenografts.
2024-09-30 | GSE236677 | GEO
Project description:Purpose: Identify new targets in MYCN-amplified Neuroblastoma Methods: ChIP-Seq experiments were performed on Kelly and LAN-1 neuroblastoma cells by using the following antibodies: anti-EZH2 (Cell Signaling 5246S); anti-H3K27me3 (Millipore 07-449); anti-H3K4me3 (Abcam ab8580). We evaluated the global EZH2 PRC2-dependence by identifiying direct genome-wide target genes for EZH2, H3K27me3 and H3K4me3. Results: We found that EZH2 serves a PRC2-dependent function in neuroblastoma, repressing neuronal differentiation. Moreover, EZH2-regulated genes were strongly repressed in MYCN-amplified and high-risk primary tumors. Conclusion: Our study supports testing EZH2 inhibitors in patients with MYCN-amplified neuroblastoma.
2017-12-02 | GSE85430 | GEO
Project description:MYCN amplification (MNA) is a defining feature of high-risk neuroblastoma (NB) that predicts poor prognosis. However, whether genes within or in close proximity to the MYCN amplicon also contribute to aggressiveness in MNA+ NB remains poorly understood. Here we identify that GREB1, a transcription factor encoding gene neighboring the MYCN locus, is frequently co-expressed with MYCN, and promotes cell survival in MNA+ NB. GREB1 controls gene expression independently of MYCN in MNA+ NB, among which we uncover Myosin 1B (MYO1B) as being highly expressed in MNA+ NB. MYO1B promotes aggressive features, including invasive capacity in vitro, as well as extravasation and distant metastasis in vivo. Global secretome and proteome profiling further delineate MYO1B as a major regulator of secretome reprogramming in MNA+ NB cells. Moreover, we identify the cytokine MIF as an important pro-invasive and pro-metastatic mediator of MYO1B activity. Together, we have identified a putative GREB1-MYO1B-MIF axis as an unconventional mechanism that promotes the aggressiveness of MNA+ NB, and independently of MYCN. Furthermore, we find that MYO1B is upregulated in association with other oncoproteins during cellular transformation, and is dramatically increased in multiple human cancer types, suggesting a crucial role of MYO1B in cancers in addition to MNA+ NB.
2023-10-24 | PXD039410 | Pride
Project description:Here we sought metabolic alterations specifically associated with amplified MYCN as nodes to indirectly target the MYCN oncogene. Liquid chromatography-mass spectrometry-based proteomics identified 7 proteins consistently correlated with MYCN in proteomes from 49 neuroblastoma biopsies and 13 cell lines. Among these were phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme in de novo serine synthesis. MYCN associated with two regions in the PHGDH promoter, supporting transcriptional PHGDH regulation by MYCN. Pulsed stable isotope-resolved metabolomics utilizing 13C-glucose labeling demonstrated higher de novo serine synthesis in MYCN-amplified cells compared to cells with diploid MYCN. An independence of MYCN-amplified cells from exogenous serine and glycine was demonstrated by serine and glycine starvation, which attenuated nucleotide pools and proliferation only in cells with diploid MYCN but did not diminish these endpoints in MYCN-amplified cells. Proliferation was attenuated in MYCN-amplified cells by CRISPR/Cas9-mediated PHGDH knockout or treatment with PHGDH small molecule inhibitors without affecting cell viability. PHGDH inhibitors administered as single-agent therapy to NMRI-Foxn1nu/nu mice harboring patient-derived MYCN-amplified neuroblastoma xenografts slowed tumor growth. However, combining a PHGDH inhibitor with the standard-of-care chemotherapy drug, cisplatin, revealed antagonism of chemotherapy efficacy in vivo. Emergence of chemotherapy resistance was confirmed in the genetic PHGDH knockout model in vitro. Altogether, PHDGH knockout and inhibition by small molecules consistently slows proliferation, but stops short of killing the cells, which then establish resistance to classical chemotherapy. Although PHGDH inhibition with small molecules has produced encouraging results in other preclinical cancer models, this approach must be considered with caution in patients with neuroblastoma.
2020-12-11 | PXD018300 | Pride
Project description:Neuroblastoma (NB) is a common neuroendocrine tumor in early childhood, and the poor prognosis of high-risk NB is due to its poorly differentiated characteristics and immunosuppressive microenvironment. Around 25% of high-risk NB in children is caused by MYCN gene amplification. In this study, we found that Branched-chain amino acid transaminase 1 (BCAT1) is overexpressed in NB, especially those with MYCN amplification, and is a positively correlated with MYCN expression. Moreover, BCAT1 may be a risk factor for NB, significantly affecting proliferation of NB cells. Besides, we revealed that MYCN directly regulated BCAT1 transcription through binding to BCAT1 promoter, thus enhancing BCAT1-MYCN cooperativity. The highly disordered loop region of the MYCN protein makes it readily degraded under natural conditions, making it difficult to obtain the real structure of MYCN through experiments. We performed GROMACs optimization on the MYCN structure obtained from Alphafold, which increased the reliability of the MYCN structure and met the requirements of subsequent protein docking experiments. In this study, we found that after BCAT1 binds to the disordered regions of MYCN, it can improve the overall stability of MYCN. Therefore, we hypothesized that BCAT1 can enhance the stability of MYCN, suggesting that BCAT1 may be a potential therapeutic target for MYCN-amplified NB. In summary, these findings establish BCAT1 is a critical oncogenic factor in NB and provide a new potential target for treatment of NB with MYCN amplification.
2025-04-01 | GSE267875 | GEO
Project description:Purpose: Clinical courses of neuroblastomas (NBs) range from rapid progression with fatal outcome despite intensive multimodality therapies to spontaneous regression. Amplified MYCN oncogene defines a subgroup with poor outcome. However, a substantial number of MYCN single-copy NBs exhibits an aggressive phenotype similar to that of MYCN-amplified NBs even in the absence of high MYCN mRNA and/or protein levels. Experimental Design: To identify shared molecular mechanisms that mediate the aggressive phenotype in MYCN amplified and single-copy high-risk NBs, we defined genetic programs evoked by ectopically expressed MYCN in vitro and analyzed them in high-risk versus low-risk NB tumors (n=49) using cDNA microarrays. Candidate gene and protein expression was validated in a separate cohort of 117 patients using quantitative PCR (QPCR) and in a panel of NB tumors using immunohistochemistry. Results: We identified a genetic signature characterized by Skp2, encoding the F-box protein of the SCFSkp2 E3-ligase, and a subset of MYCN and of E2F targets to be highly expressed in high-risk NBs. We validated the findings for Skp2 and analyzed its expression in relation to MYCN and E2F-1 expression in a separate cohort (n=117) using QPCR. Most importantly, high Skp2 expression proved to be a highly significant marker of dire prognosis independent of both MYCN status and disease stage, on the basis of multivariate analysis of event-free survival (hazard ratio, 3.54
2007-06-01 | E-CVDE-2 | biostudies-arrayexpress
Project description:To evaluate the expression of genes associated with MYCN in NB, 10 tumors with MYCN amplification and 10 with normal MYCN copy number were subjected to oligonucleotide microarray using Agilent oligo microarray chips.
2013-12-17 | GSE53371 | GEO