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BCAT1-Mediated N-Myc Stabilization Contributes to Tumorigenesis of MYCN-Amplified Neuroblastoma

ABSTRACT: BCAT1-Mediated N-Myc Stabilization Contributes to Tumorigenesis of MYCN-Amplified Neuroblastoma

PROVIDER: PRJNA1113576 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR29084053_1.fastq.gz	Fastqsanger.gz
	SRR29084053_2.fastq.gz	Fastqsanger.gz
	SRR29084054_1.fastq.gz	Fastqsanger.gz
	SRR29084054_2.fastq.gz	Fastqsanger.gz
	SRR29084055_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

BCAT1-Mediated N-Myc Stabilization Contributes to Tumorigenesis of MYCN-Amplified Neuroblastoma

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

The Super Elongation Complex Drives Transcriptional Addiction in MYCN-amplified Neuroblastoma

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

Neuroblastoma: MYCN normal vs. MYCN amplified

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

Genome-wide binding of MYCN protein in MYCN-amplified neuroblastoma cell lines

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

Targeting EZH2 in MYCN-amplified Neuroblastoma

Project description:Targeting EZH2 in MYCN-amplified Neuroblastoma

| PRJNA338446 | ENA

Metabolic dependencies in MYCN-driven neuroblastoma

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

Targeting EZH2 in MYCN-amplified Neuroblastoma [ChIP-seq]

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

miRNA profiling of MYCN-amplified Neuroblastoma cell lines

Project description:miRNA expression levels have been profiled on 13 MYCN-amplified Neuroblastoma cell lines

2015-09-24 | GSE56655 | GEO

RNA-sequencing in two MYCN amplified/high-risk and one non-MYCN amplified/low-risk neuroblastoma cell lines

Project description:RNA-sequencing has been used to obtain and observe transcriptome-wide differences that occur in two parasspeckle-deficient, MYCN-amplified/model high-risk and one paraspeckle-abundant, non-MYCN-amplified/low-risk cell lines, to decipher the role of paraspeckles in this cancer type.

2021-09-09 | GSE133552 | GEO

aCGH profiling of MYCN-amplified Neuroblastoma cell lines

Project description:Genome copy-number status has been profiled on 13 MYCN-amplified Neuroblastoma cell lines

2015-09-24 | GSE56654 | GEO