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OmoMYC blunts promoter invasion by oncogenic MYC to inhibit gene expression characteristic of MYC-dependent tumors

ABSTRACT: OmoMYC blunts promoter invasion by oncogenic MYC to inhibit gene expression characteristic of MYC-dependent tumors

PROVIDER: PRJNA310063 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR3130250.fastq.gz	Fastqsanger.gz
	SRR3130260.fastq.gz	Fastqsanger.gz
	SRR3130270.fastq.gz	Fastqsanger.gz
	SRR3130280.fastq.gz	Fastqsanger.gz
	SRR3130251.fastq.gz	Fastqsanger.gz

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Similar Datasets

OmoMYC blunts promoter invasion by oncogenic MYC to inhibit gene expression characteristic of MYC-dependent tumors

Project description:MYC genes have both essential roles during normal development and exert oncogenic functions during tumorigenesis. Expression of a dominant-negative allele of MYC, termed OmoMYC, can induce rapid tumor regression in mouse models with little toxicity for normal tissues. How OmoMYC discriminates between physiological and oncogenic functions of MYC is unclear. We have solved the crystal structure of OmoMYC and show that it forms a stable homodimer and as such recognizes DNA in the same manner as the MYC/MAX heterodimer. OmoMYC attenuates both MYC-dependent activation and repression by competing with MYC/MAX for binding to chromatin, effectively lowering MYC/MAX occupancy at its cognate binding sites. OmoMYC causes the largest decreases in promoter occupancy and changes in expression on genes that are invaded by oncogenic MYC levels. A signature of OmoMYC-regulated genes defines subgroups with high MYC levels in multiple tumor entities and identifies novel targets for the eradication of MYC-driven tumors.

2016-10-18 | GSE77328 | GEO

Effect of Omomyc treatment on MYC mediated transcription

Project description:Purpose: Identify MYC sensitive enes that are affected by treatment with Omomyc

2019-09-01 | GSE131075 | GEO

Transcriptional response to serum stimulation of Rat1 fibroblasts in the presence or absence of the Myc interfering molecule termed Omomyc.

Project description:Myc is a multifaceted bHLHZip transcription factor deregulated in the majority of human cancers. How to target Myc for cancer therapy is unclear, given its involvement in a variety of key functions in healthy cells. We used microarrays to capture the cellular transcriptional response to Omomyc – a Myc interfering molecule acting at the level of protein protein interactions that demonstrated a remarkable therapeutic efficacy in transgenic mouse cancer models. We found that Omomyc differently affects Myc induced gene repression and activation, channelling the Myc interactome activity to repression. To determine whether Omomyc causes widespread changes of the cell transcriptome, we analysed the transcriptional response to serum stimulation of Rat1 fibroblasts stably infected with an Omomer – Omomyc fused to the tamoxifen inducible oestrogen receptor ERTM – producing retrovirus (Rat1_Omomer) as compared to Rat1 cells infected with a control virus (Rat1_Control). Endogenous c-Myc is known to be sharply induced by serum and is critical for cell cycle re-entry. Cells were grown, serum-starved for 48 h in presence of tamoxifen (4-OHT) and stimulated by addition of fresh serum. Total RNA was collected from Rat1_Control and Rat1-Omomer cells at the time of serum re-addition (T0) and 90' thereafter (T90'), in the presence of tamoxifen.

2010-12-21 | E-GEOD-25039 | biostudies-arrayexpress

Genome-wide chromatin binding of MYC, Omomyc, RNA polymerase II (Pol II), and Pol II Ser-2p in human glioblastoma cells and glioblastoma stem cells expressing or not Omomyc

Project description:MYC deregulation is common in human cancer and has a role in sustaining the aggressive cancer stem cell populations. MYC mediates a broad transcriptional response controlling normal biological programs but its activity is not clearly understood. We address MYC function in cancer stem cells through the inducible expression of Omomyc – a MYC derived polypeptide interfering with MYC activity – taking as model the most lethal brain tumor, glioblastoma. Omomyc bridles the key cancer stem-like cell features and affects tumor microenvironment, inhibiting angiogenesis. This occurs because Omomyc interferes with proper Myc localization and binds to DNA, with a preference for sites previously occupied by MYC. This is accompanied by (leads to) selective repression of master transcription factors for glioblastoma stem-like cell identity like POU3F2, SOX2, and OLIG2, upregulation of effectors of tumor suppression and differentiation such as PTEN, ID4, MIAT, and modulation of the expression of microRNAs that target molecules implicated in glioblastoma growth and invasion like EGFR and ZEB1. Data support a novel view of MYC as a network stabilizer that strengthens the regulatory nodes of the gene expression programs controlling cell phenotype and highlight Omomyc as model molecule for targeting cancer stem cells.

2016-11-16 | GSE86511 | GEO

Utilizing Omomyc to Target MYCN-Amplified Diffuse Intrinsic Pontine Gliomas

Project description:Genomic studies have shown that several types of pediatric brain tumors have dysregulation of MYC family members (c-MYC and MYCN). In fact, it has been estimated that about 50% of all human cancers have increased MYC, and this is correlated with tumor aggression and poor survival. Here we focus on targeting the MYCN oncogene in diffuse intrinsic pontine glioma (DIPG). DIPG has the worst prognosis of any pediatric brain tumor and is in desperate need of viable treatment options. Here we demonstrate that using a 90-amino acid peptide, termed “Omomyc” we are able to down-regulate endogenous MYCN and inhibit growth of MYCN overexpressing DIPG cells. Furthermore, Omomyc binds to promoter regions normally occupied by MYCN to affect transcription of a subset of genes including PLK1 and LDHA, among others. In vivo expression of Omomyc in DIPG cells implanted in mice slows disease progression, suggesting that MYCN targets are important for driving rapid tumor growth and may offer insight into potential targets for treatment of MYCN driven DIPGs.

2023-12-01 | GSE201936 | GEO

Transcriptional response to serum stimulation of Rat1 fibroblasts in the presence or absence of the Myc interfering molecule termed Omomyc.

2010-12-21 | GSE25039 | GEO

Effect of Omomyc treatment on MYC mediated transcription

Project description:Effect of Omomyc treatment on MYC mediated transcription

| PRJNA542602 | ENA

Effect of Omomyc on lymph node metastases from melanomas [SkMel147]

Project description:Skin melanomas are highly aggressive and metastatic. Omomyc is the best MYC inhibitor currently available. We analysed the effect of Omomyc expression in a transgenic and inducible (upon Doxycycline addition) manner in spontaneous lymph node metastases from SkMel147 (mutated in NRAS) melanoma cells in vivo. We used microarrays to detail the change in the gene expression programs induced by Omomyc on day 2.

2023-04-09 | GSE227843 | GEO

Effect of Omomyc on the in vivo growth of melanomas

Project description:Skin melanomas are highly aggressive and metastatic. Omomyc is the best MYC inhibitor currently available. We analysed the effect of Omomyc expression in a transgenic and inducible (upon Doxycycline addition) manner in melanoma cells in vivo in two different melanoma cell lines: A375 (mutated in BRAF), SkMel147 (mutated in NRAS). We used microarrays to detail the change in the gene expression programs induced by Omomyc on day 7.

2023-04-09 | GSE227841 | GEO

Omomyc Reveals New Mechanisms To Inhibit the MYC Oncogene.

Project description:The MYC oncogene is upregulated in human cancers by translocation, amplification, and mutation of cellular pathways that regulate Myc. Myc/Max heterodimers bind to E box sequences in the promoter regions of genes and activate transcription. The MYC inhibitor Omomyc can reduce the ability of MYC to bind specific box sequences in promoters of MYC target genes by binding directly to E box sequences as demonstrated by chromatin immunoprecipitation (CHIP). Here, we demonstrate by both a proximity ligation assay (PLA) and double chromatin immunoprecipitation (ReCHIP) that Omomyc preferentially binds to Max, not Myc, to mediate inhibition of MYC-mediated transcription by replacing MYC/MAX heterodimers with Omomyc/MAX heterodimers. The formation of Myc/Max and Omomyc/Max heterodimers occurs cotranslationally; Myc, Max, and Omomyc can interact with ribosomes and Max RNA under conditions in which ribosomes are intact. Taken together, our data suggest that the mechanism of action of Omomyc is to bind DNA as either a homodimer or a heterodimer with Max that is formed cotranslationally, revealing a novel mechanism to inhibit the MYC oncogene. We find that in vivo, Omomyc distributes quickly to kidneys and liver and has a short effective half-life in plasma, which could limit its use in vivo.

| S-EPMC6817756 | biostudies-literature

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