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MYCN directly regulates TET1 expression to control 5-hmC distribution and enhance neuroblastoma cell migration in hypoxia [RNA-Seq]

ABSTRACT: We performed RNA-sequencing on inducible MYCN cell line SHEPTET21n on Day 4 post MYCN induction

ORGANISM(S): Homo sapiens

PROVIDER: GSE167476 | GEO | 2022/08/10

REPOSITORIES: GEO

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MYCN directly regulates TET1 expression to control 5-hmC distribution and enhance neuroblastoma cell migration in hypoxia

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-08-10 | GSE167478 | GEO

MYCN and HIF-1 directly regulate <i>TET1</i> expression to control 5-hmC gains and enhance neuroblastoma cell migration in hypoxia.

Project description:Ten-Eleven-Translocation 5-methylcytosine dioxygenases 1-3 (TET1-3) convert 5-methylcytosine to 5-hydroxymethylcytosine (5-hmC), using oxygen as a co-substrate. Contrary to expectations, hypoxia induces 5-hmC gains in MYCN-amplified neuroblastoma (NB) cells via upregulation of TET1. Here, we show that MYCN directly controls TET1 expression in normoxia, and in hypoxia, HIF-1 augments TET1 expression and TET1 protein stability. Through gene-editing, we identify two MYCN and HIF-1 binding sites within TET1 that regulate gene expression. Bioinformatic analyses of 5-hmC distribution and RNA-sequencing data from hypoxic cells implicate hypoxia-regulated genes important for cell migration, including CXCR4. We show that hypoxic cells lacking the two MYCN/HIF-1 binding sites within TET1 migrate slower than controls. Treatment of MYCN-amplified NB cells with a CXCR4 antagonist results in slower migration under hypoxic conditions, suggesting that inclusion of a CXCR4 antagonist into NB treatment regimens could be beneficial for children with MYCN-amplified NBs.

| S-EPMC9665154 | biostudies-literature

MYCN directly regulates TET1 expression to control 5-hmC distribution and enhance neuroblastoma cell migration in hypoxia [ChIP-Seq]

Project description:We performed HIF-1alpha ChIP-seq in SK-N-BE(2) cells cultured in normoxia vs. hypoxia for 48 hrs. We identified two new HIF-1alpha binding sites in TET1 that control TET1expression in hypoxia

2022-08-10 | GSE167477 | GEO

MYCN directly regulates TET1 expression to control 5-hmC distribution and enhance neuroblastoma cell migration in hypoxia [hMe-SEAL]

Project description:We characterized genome-wide 5-hydroxymerhylcytosine (5-hmC) distribution at 0,6,12,24, 48, 72 hours in hypoxia in SK-N-BE(2) neuroblastoma cell line.5-hmC increases over time in hypoxic but especially between 0 and 6 and 24 to 48 hours.

2022-08-10 | GSE167475 | GEO

MYCN directly regulates TET1 expression to control 5-hmC distribution and enhance neuroblastoma cell migration in hypoxia

Project description:MYCN directly regulates TET1 expression to control 5-hmC distribution and enhance neuroblastoma cell migration in hypoxia

| PRJNA704703 | ENA

MYCN directly regulates TET1 expression to control 5-hmC distribution and enhance neuroblastoma cell migration in hypoxia [ChIP-Seq]

Project description:MYCN directly regulates TET1 expression to control 5-hmC distribution and enhance neuroblastoma cell migration in hypoxia [ChIP-Seq]

| PRJNA704704 | ENA

MYCN directly regulates TET1 expression to control 5-hmC distribution and enhance neuroblastoma cell migration in hypoxia [RNA-Seq]

Project description:MYCN directly regulates TET1 expression to control 5-hmC distribution and enhance neuroblastoma cell migration in hypoxia [RNA-Seq]

| PRJNA704705 | ENA

MYCN directly regulates TET1 expression to control 5-hmC distribution and enhance neuroblastoma cell migration in hypoxia [hMe-SEAL]

Project description:MYCN directly regulates TET1 expression to control 5-hmC distribution and enhance neuroblastoma cell migration in hypoxia [hMe-SEAL]

| PRJNA704701 | ENA

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

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

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