Disruption of KLHL37-N-Myc complex restores N-Myc degradation and arrests neuroblastoma growth in mouse models
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1252111 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR33206741_1.fastq.gz | Fastqsanger.gz | |||
| SRR33206741_2.fastq.gz | Fastqsanger.gz | |||
| SRR33206742_1.fastq.gz | Fastqsanger.gz | |||
| SRR33206742_2.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 13 |
Similar Datasets
Project description:MYCN amplification accounts for the most common genetic aberration in neuroblastoma and strongly predicts the aggressive progression and poor clinical prognosis. However, clinically effective therapies that directly target N-Myc activity are limited. N-Myc is a transcription factor, and its stability are tightly controlled by ubiquitination-dependent proteasomal degradation. Here, we discovered that Kelch-like protein 37 (KLHL37) played a crucial role in enhancing the protein stability of N-Myc in neuroblastoma. KLHL37 directly interacted with N-Myc to disrupt the N-Myc/FBXW7 interaction, thereby stabilizing N-Myc and enabling tumor progression. Suppressing KLHL37 effectively induced the degradation of N-Myc and exhibited a profound inhibitory effect on the growth of MYCN-amplified neuroblastoma. Notably, we identified RTA-408 as an inhibitor of KLHL37 to disrupt KLHL37-N-Myc complex, promoting the degradation of N-Myc and suppressing neuroblastoma in vivo and in vitro. Moreover, we elucidated the therapeutic potential of RTA-408 for neuroblastoma by utilizing the PDC and PDX tumor models. RTA408's anti-tumor effects may not be exclusively via KLHL37, and specific KLHL37 inhibitors are expected to be developed in the future. These findings not only uncover the biological function of KLHL37 in regulating N-Myc stability, but also indicate that KLHL37 inhibition is a promising therapeutic regimen for neuroblastoma, especially in MYCN-amplified patients.
2025-06-17 | GSE294960 | GEO
Project description:Efforts to therapeutically target EZH2 have generally focused on inhibition of its methyltransferase activity, although it remains less clear whether this is the central mechanism whereby EZH2 promotes cancer. We demonstrate that EZH2 directly interacts with both MYC family oncoproteins, MYC and MYCN, and promotes their stabilization in a methyltransferase-independent manner. By competing against the SCFFBW7 ubiquitin ligase to bind MYC and MYCN, EZH2 counteracted FBW7-mediated MYC(N) polyubiquitination and proteasomal degradation. Depletion, but not enzymatic inhibition, of EZH2 induced robust MYC(N) degradation and inhibited tumor cell growth in MYC(N) driven neuroblastoma and small cell lung cancer. These findings unveil the MYC family proteins as global EZH2 oncogenic effectors and EZH2 pharmacologic degraders as potential MYC(N) targeted cancer therapeutics, pointing out that MYC(N) driven cancers may develop inherent resistance to the canonical EZH2 enzymatic inhibitors currently in clinical development.
2022-02-17 | PXD029652 | Pride
Project description:Efforts to therapeutically target EZH2 have generally focused on inhibition of its methyltransferase activity, although it remains less clear whether this is the central mechanism whereby EZH2 promotes cancer. We demonstrate that EZH2 interacts with both MYC family oncoproteins, C-MYC and N-MYC, and promotes their stabilization in a methyltransferase-independent manner. By competing against the SCFFbw7 ubiquitin ligase to bind MYC, EZH2 counteracted Fbw7-mediated MYC polyubiquitination and proteasomal degradation. Depletion, but not enzymatic inhibition, of EZH2 induced robust MYC degradation and inhibited tumor cell growth in MYC-driven neuroblastoma and small-cell lung cancer. These findings unveil the MYC family proteins as critical EZH2 oncogenic effectors and EZH2 pharmacologic degraders as potential MYC-selective cancer therapeutics, pointing out that MYC-driven cancers may develop inherent resistance to canonical EZH2 enzymatic inhibitors currently in clinical development.
2021-08-31 | GSE181782 | GEO
Project description:The oncogene MYC drives many cancers and is an outstanding therapeutic target. MYC is an intrinsically disordered protein, and therefore, targeting MYC remains a challenge. Here, we developed a proteolysis targeting chimera (PROTAC) degrading MYC: MDEG-541. The inhibitor is based on the MYC-MAX dimerization inhibitor 10058-F4 and Thalidomide. Mode of action depends on the proteasome and cereblon. MDEG-541 shows single digit mM activity in most sensitive colon and pancreatic cancer cell lines as well as gastrointestinal tumor organoids.
2022-05-12 | PXD018674 | Pride
Project description:The molecular circadian clock, which controls rhythmic 24-hour oscillation of genes, proteins, and metabolites, is disrupted across many human cancers. Deregulated expression of MYC oncoprotein has been shown to alter expression of molecular clock genes, leading to a disruption of molecular clock oscillation across cancer types. It remains unclear what benefit cancer cells gain from suppressing clock oscillation, and how this loss of molecular clock oscillation impacts global gene expression and metabolism in cancer. We hypothesized that MYC suppresses oscillation of gene expression and metabolism to instead upregulate pathways involved in biosynthesis in a static, non-oscillatory fashion. To test this, cells from distinct cancer types with inducible MYC or the closely related N-MYC were examined, using detailed time-series RNA-sequencing and metabolomics, to determine the extent to which MYC activation disrupts global oscillation of genes, gene expression, programs, and metabolites. We focused our analyses on genes, pathways, and metabolites that changed in common across multiple cancer cell line models. We report here that MYC disrupted over 85% of oscillating genes, while instead promoting enhanced ribosomal and mitochondrial biogenesis and suppressed cell attachment pathways. Notably, when MYC is activated, biosynthetic programs that were formerly circadian flipped to being upregulated in an oscillation-free manner. Further, activation of MYC ablates the oscillation of nutrient transporter proteins while greatly upregulating transporter expression, cell surface localization, and intracellular amino acid pools. Finally, we report that MYC disrupts metabolite oscillations and the temporal segregation of amino acid metabolism from nucleotide metabolism. Our results demonstrate that MYC disruption of the molecular circadian clock releases metabolic and biosynthetic processes from circadian control, which may provide a distinct advantage to cancer cells.
2023-07-18 | GSE237608 | GEO
Project description:Targeting Processive Transcription Elongation via SEC Disruption for MYC-Induced Cancer Therapy
| PRJNA448451 | ENA
Project description:A novel tumor suppressing role for RUNX3 is shown where a direct interaction with MYC leads to disruption of MYC-MAX heterodimers and consequent degradation of the MYC oncoprotein
| PRJNA977962 | ENA
Project description:Deregulated expression of MYC enhances glutamine utilization and renders cell survival dependent on glutamine, inducing “glutamine addiction”. Surprisingly, colon cancer cells that express high levels of MYC due to WNT pathway mutations, are not glutamine-addicted but undergo a reversible cell cycle arrest upon glutamine deprivation. We show here that glutamine deprivation suppresses translation of endogenous MYC via the 3’-UTR of the MYC mRNA, enabling escape from apoptosis. This regulation is mediated by glutamine-dependent changes in adenosine nucleotide levels. Glutamine deprivation causes a global reduction in promoter association of RNA Polymerase II (RNAPII) and slows transcriptional elongation. While activation of MYC restores binding of MYC and RNAPII function on most promoters, restoration of elongation is imperfect and activation of MYC in the absence of glutamine causes stalling of RNAPII on multiple genes, correlating with R-loop formation. Stalling of RNAPII and R-loop formation can cause DNA damage, arguing that the MYC 3’-UTR is critical for maintaining genome stability when ribonucleotide levels are low.
2022-02-28 | PXD005829 | Pride
Project description:The molecular circadian clock, which controls rhythmic 24-hour oscillation of genes, proteins, and metabolites, is disrupted across many human cancers. Deregulated expression of MYC oncoprotein has been shown to alter expression of molecular clock genes, leading to a disruption of molecular clock oscillation across cancer types. However, it remained unclear how this loss of molecular clock oscillation impacted global gene expression and metabolism in cancer, and what benefit cancer cells might gain from suppressing clock oscillation. We hypothesized that MYC suppresses oscillation of gene expression and metabolism to instead upregulate pathways involved in biosynthesis in a static, non-oscillatory fashion. To test this, we utilized cells from distinct cancer types with inducible MYC or the closely related N-MYC to determine, using detailed time-series RNA-sequencing and metabolomics, the extent to which MYC activation disrupts global oscillation of genes, gene expression, programs, and metabolites. We focused our analyses on genes, pathways, and metabolites that changed in common across multiple cancer cell line models. We report here that MYC disrupted over 85% of oscillating genes, while instead promoting enhanced ribosomal and mitochondrial biogenesis and suppressed cell attachment pathways. Notably, when MYC is activated, biosynthetic programs that were formerly circadian flipped to being upregulated in an oscillation-free manner. Further, activation of MYC ablates the oscillation of nutrient transporter glycosylation while greatly upregulating transporter expression, cell surface localization, and intracellular amino acid pools. Finally, we report that MYC disrupts metabolite oscillations and the temporal segregation of amino acid metabolism from nucleotide metabolism. Our results demonstrate that MYC disruption of the molecular circadian clock releases metabolic and biosynthetic processes from circadian control, which may provide a distinct advantage to cancer cells.
2023-01-03 | GSE221103 | GEO
Project description:[This corrects the article DOI: 10.1371/journal.pone.0096343.].
| S-EPMC4934772 | biostudies-literature