Silencing of the Long Noncoding RNA MYCNOS1 Suppresses Activity of MYCN-Amplified Retinoblastoma Without RB1 Mutation
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ABSTRACT:
PROVIDER: PRJNA678350 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13057916_1.fastq.gz | Fastqsanger.gz | |||
| SRR13057916_2.fastq.gz | Fastqsanger.gz | |||
| SRR13057917_1.fastq.gz | Fastqsanger.gz | |||
| SRR13057917_2.fastq.gz | Fastqsanger.gz | |||
| SRR13057918_1.fastq.gz | Fastqsanger.gz |
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Project description:MYCNOS (MYCN opposite strand) is co-amplified with MYCN in pediatric cancers including retinoblastoma. MYCNOS encodes several RNA variants whose functions have not been elucidated in retinoblastoma. Here, we attempted to decipher the role of MYCNOS variant 1 (MYCNOS1) on the activity of MYCN-amplified retinoblastoma. We observed that MYCNOS1 supports progression of retinoblastoma. Inhibition of MYCNOS1 expression may be needed to suppress MYCN activity when treating MYCN-amplified cancers without RB1 mutation.
2020-12-15 | GSE161449 | GEO
Project description:Retinoblastoma (RB) is a common malignancy that primarily affects pediatric populations. Although a well-known cause of RB is RB1 mutation, MYCN amplification can also lead to the disease, which is a poor prognosis factor. Studies conducted in various tumor types have shown that MYCN inhibition is an effective approach to impede tumor growth. Various indirect approaches have been developed to overcome the difficulty of directly targeting MYCN, such as modulating the super enhancer (SE) upstream of MYCN. The drug used in this study to treat MYCN-amplified RB was THZ1, a CDK7 inhibitor that can effectively suppress transcription by interfering with the activity of SEs. The study findings confirmed the anticancer activity of THZ1 against RB in both in vitro and in vivo experiments. Therapy with THZ1 was found to affect numerous genes in RB according to the RNA-seq analysis. Moreover, the gene expression changes induced by THZ1 treatment were enriched in ribosome, endocytosis, cell cycle, apoptosis, etc. Furthermore, the combined analysis of ChIP-Seq and RNA-seq data suggested a potential role of SEs in regulating the expression of critical transcription factors, such as MYCN, OTX2, and SOX4. Moreover, ChIP‒qPCR experiments were conducted to confirm the interaction between MYCN and SEs. In conclusion, THZ1 caused substantial changes in gene transcription in RB, resulting in inhibited cell proliferation, interference with the cell cycle, and increased apoptosis. The efficacy of THZ1 is positively correlated with the degree of MYCN amplification and is likely exerted by interfering with MYCN upstream SEs.
2023-07-04 | GSE236205 | GEO
Project description:Effect of CDK7 inhibitor on MYCN-amplified retinoblastoma
| PRJNA989247 | ENA
Project description:The aims of this study are to compare transcripts that are differentially expressed in the MYCN amplified compare to the MYCN non-amplified neuroblastoma cell lines, in particular, long non-coding RNAs. Methods: Ribosomal depleted RNAs from six human neuroblastoma cell lines were subjected to deep sequencing, using Illumina Hiseq. Results: We identified 459 transcripts are differentially expressed betweeen the MYCN amplified and the MYCN non-amplified cell lines. Conclusions: We have identified a novel long noncoding RNA lncNB1 that is highly expressed in the MYCN amplified compared to the MYCN non-amplified cell lines.
2019-10-08 | GSE114053 | 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
Project description:PurposeMYCNOS (MYCN opposite strand) is co-amplified with MYCN in pediatric cancers, including retinoblastoma. MYCNOS encodes several RNA variants whose functions have not been elucidated in retinoblastoma. Thus, we attempted to identify MYCNOS variants in retinoblastoma and aimed to decipher the role of MYCNOS variant 1 (MYCNOS1) on the activity of MYCN-amplified retinoblastoma.MethodsThe profiles of MYCNOS variants and MYCN status were determined in 17 retinoblastoma tissues, cell lines, retinas, and retinal organoids. A functional study of MYCNOS1 expression was conducted in patient-derived tumor cells and in retinoblastoma cell lines via short hairpin RNA-mediated gene silencing. We carried out MYCN expression, cell viability, cell cycle, apoptosis, soft agar colony formation, and transwell assays to examine the role of MYCNOS1 in MYCN and cell behaviors. We analyzed a transcriptome of MYCN-amplified retinoblastoma cells deficient for MYCNOS1 and, finally, tested the responses of these cells to chemotherapeutic agents.ResultsExpression of MYCNOS1 was associated with the expression and copy number of MYCN. Knockdown of MYCNOS1 caused instability of the MYCN protein, leading to cell cycle arrest and impaired proliferation and chemotaxis-directed migration in MYCN-amplified retinoblastoma cells in which RB1 was intact. MYCNOS1 expression was associated with gene signatures of photoreceptor cells and epithelial-mesenchymal transition. MYCNOS1 silencing enhanced the response of retinoblastoma cells to topotecan but not carboplatin.ConclusionsMYCNOS1 supports progression of retinoblastoma. Inhibition of MYCNOS1 expression may be necessary to suppress MYCN activity when treating MYCN-amplified cancers without RB1 mutation.
| S-EPMC7718827 | biostudies-literature
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:Retinoblastoma is a rare childhood cancer of the developing retina. Most retinoblastomas initiate with biallelic inactivation of the RB1 gene through diverse mechanisms including point mutations, nucleotide insertions, deletions, loss of heterozygosity and promoter hypermethylation. Recently, a novel mechanism of retinoblastoma initiation was proposed. Gallie and colleagues discovered that a small proportion of retinoblastomas lack RB1 mutations and had MYCN amplification [1]. In this study, we identified recurrent chromosomal, regional and focal genomic lesions in 94 primary retinoblastomas with their matched normal DNA using SNP 6.0 chips. We also analyzed the RB1 gene mutations and compared the mechanism of RB1 inactivation to the recurrent copy number variations in the retinoblastoma genome. In addition to the previously described focal amplification of MYCN and deletions in RB1 and BCOR, we also identified recurrent focal amplification of OTX2, a transcription factor required for retinal photoreceptor development. We identified 10 retinoblastomas in our cohort that lacked RB1 point mutations or indels. We performed whole genome sequencing on those 10 tumors and their corresponding germline DNA. In one of the tumors, the RB1 gene was unaltered, the MYCN gene was amplified and RB1 protein was expressed in the nuclei of the tumor cells. In addition, several tumors had complex patterns of structural variations and we identified 3 tumors with chromothripsis at the RB1 locus. This is the first report of chromothripsis as a mechanism for RB1 gene inactivation in cancer.
| EGAS00001000598 | EGA
Project description:Retinoblastoma are childhood eye tumors arising from retinal precursor cells. Two distinct retinoblastoma subtypes with different clinical behavior have been described based on gene expression and methylation profiling. Using consensus clustering of DNA methylation analysis from retinoblastomas, we identified a MYCN-driven cluster of subtype 2 retinoblastomas characterized by DNA hypomethylation and high expression of genes involved in protein synthesis. Subtype 2 retinoblastomas outside the MYCN-driven cluster were characterized by high expression of genes from mesodermal development, including NKX2-5. Knockdown of MYCN expression in retinoblastoma cell models caused growth arrest and reactivated a subtype 1-specific photoreceptor signature. These molecular changes suggest that removing the driving force of MYCN oncogenic activity rescues molecular circuitry driving subtype 1 biology. The MYCN-RB gene signature generated from the cell models better identified MYCN-driven retinoblastoma than MYCN amplification and could identify cases that may benefit from MYCN-targeted therapy. MYCN drives tumor progression in a molecularly defined retinoblastoma subgroup, and inhibiting MYCN activity could restore a more differentiated and less aggressive tumor biology
2024-05-31 | GSE267015 | GEO
Project description:Retinoblastoma are childhood eye tumors arising from retinal precursor cells. Two distinct retinoblastoma subtypes with different clinical behavior have been described based on gene expression and methylation profiling. Using consensus clustering of DNA methylation analysis from retinoblastomas, we identified a MYCN-driven of subtype 2 retinoblastomas characterized by DNA hypomethylation and high expression of genes involved in protein synthesis. Subtype 2 retinoblastomas outside the MYCN-driven were characterized by high expression of genes from mesodermal development, including NKX2-5. Knockdown of MYCN expression in retinoblastoma cell models caused growth arrest and reactivated a subtype 1-specific photoreceptor signature. These molecular changes suggest that removing the driving force of MYCN oncogenic activity rescues molecular circuitry driving subtype 1 biology. The MYCN-RB gene signature generated from the cell models better identified MYCN-driven retinoblastoma than MYCN amplification and could identify cases that may benefit from MYCN-targeted therapy. MYCN drives tumor progression in a molecularly defined retinoblastoma subgroup, and inhibiting MYCN activity could restore a more differentiated and less aggressive tumor biology
2024-05-31 | GSE268136 | GEO