Endothelial-specific c-Myc depletion enhances diet-induced liver inflammation and fibrosis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA736726 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14780700.fastq.gz | Fastqsanger.gz | |||
| SRR14780701.fastq.gz | Fastqsanger.gz | |||
| SRR14780702.fastq.gz | Fastqsanger.gz | |||
| SRR14780703.fastq.gz | Fastqsanger.gz | |||
| SRR14780704.fastq.gz | Fastqsanger.gz |
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Project description:Endothelial cells play an essential role in inflammation through synthesis and secretion of chemoattractant cytokines and expression of adhesion molecules required for inflammatory cell attachment and infiltration. The mechanisms by which endothelial cells control its pro-inflammatory response depends on the type of inflammatory stimuli, endothelial cell origin and tissue involved. In the present study, we investigate the role of the transcription factor c-Myc in inflammation using a conditional knockout mouse model in which Myc is specifically deleted in the endothelium (EC-Myc KO). Using an experimental model of nonalcoholic steatohepatitis, we investigated the involvement of endothelial c-Myc in diet-induced inflammation. EC-Myc KO animals displayed enhanced pro-inflammatory response relative to control, which was characterized by increased expression of pro-inflammatory cytokines and leukocyte infiltration as well as worsened liver fibrosis. Transcriptome analysis suggested that different pro-inflammatory pathways are activated in control and endothelial Myc knockout after exposure to high-fat diet. Analysis of published single cell RNA-sequencing data available on human cirrhotic livers indicated that MYC was downregulated in endothelial cells relative to healthy individuals. Our results suggest a protective role for endothelial c-Myc in diet-induced liver inflammation and fibrosis. Targeting c-Myc and its downstream pathways in the endothelium may be a promising strategy for treatment of diet-induced inflammatory disease.
2022-06-30 | GSE176573 | GEO
Project description:Endothelial cells play an essential role in inflammation through synthesis and secretion of chemoattractant cytokines and expression of adhesion molecules required for inflammatory cell attachment and infiltration. The mechanisms by which endothelial cells control the pro-inflammatory response depend on the type of inflammatory stimuli, endothelial cell origin, and tissue involved. In the present study, we investigated the role of the transcription factor c-Myc in inflammation using a conditional knockout mouse model in which Myc is specifically deleted in the endothelium. At a systemic level, circulating monocytes, the chemokine CCL7, and the extracellular-matrix protein osteopontin were significantly increased in endothelial c-Myc knockout (EC-Myc KO) mice, whereas the cytokine TNFSF11 was downregulated. Using an experimental model of steatohepatitis, we investigated the involvement of endothelial c-Myc in diet-induced inflammation. EC-Myc KO animals displayed enhanced pro-inflammatory response, characterized by increased expression of pro-inflammatory cytokines and leukocyte infiltration, and worsened liver fibrosis. Transcriptome analysis identified enhanced expression of genes associated with inflammation, fibrosis, and hepatocellular carcinoma in EC-Myc KO mice relative to control (CT) animals after short-exposure to high-fat diet. Analysis of a single-cell RNA-sequencing dataset of human cirrhotic livers indicated downregulation of MYC in endothelial cells relative to healthy controls. In summary, our results suggest a protective role of endothelial c-Myc in diet-induced liver inflammation and fibrosis. Targeting c-Myc and its downstream pathways in the endothelium may constitute a potential strategy for the treatment of inflammatory disease.
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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.
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Project description:Tumours depend on altered rates of protein synthesis for growth and survival, suggesting that mechanisms controlling mRNA translation may be exploitable for therapy. Here, we show that loss of APC, which occurs almost universally in colorectal tumours, strongly enhances the dependence on the translation initiation factor eIF2B5. Depletion of eIF2B5 induces an integrated stress response and enhances translation of MYC via an internal ribosomal entry site. This perturbs cellular amino acid and nucleotide pools and strains energy resources and causes MYC-dependent apoptosis. eIF2B5 limits MYC expression and prevents apoptosis in APC-deficient murine and patient-derived organoids and in APC-deficient murine intestinal epithelia in vivo. Conversely, the high MYC levels present in APC-deficient cells induce phosphorylation of eIF2alpha via the GCN2 and PKR kinases. Pharmacological inhibition of GCN2 phenocopies eIF2B5 depletion and has therapeutic efficacy in tumour organoids, demonstrating that a negative MYC/eIF2alpha feedback loop constitutes a targetable vulnerability of colorectal tumours.
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2019-08-22 | MTBLS135 | MetaboLights
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2020-03-16 | E-MTAB-8792 | biostudies-arrayexpress
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.
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