Methionine metabolism and the NOP2 methyltransferase are essential for MYC-Driven liver tumorigenesis
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ABSTRACT:
PROVIDER: PRJNA886759 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21793374_1.fastq.gz | Fastqsanger.gz | |||
| SRR21793374_2.fastq.gz | Fastqsanger.gz | |||
| SRR21793375_1.fastq.gz | Fastqsanger.gz | |||
| SRR21793375_2.fastq.gz | Fastqsanger.gz | |||
| SRR21793376_1.fastq.gz | Fastqsanger.gz |
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Project description:Hepatocellular carcinoma (HCC) represents the third leading cause of cancer-related death worldwide and has been increasing in recent years in developed nations.1,2 The MYC oncogene or its paralogs are frequently amplified or overexpressed in particularly aggressive subtypes of cancer associated with stem cell-like features and worse clinical outcomes,3,4 including in liver cancer.5 Unfortunately, selective inhibitors that target MYC or its transcriptional program are not yet clinically available for therapy of HCC. Here, we identified methionine metabolism as a selective vulnerability for MYC but not RAS-driven liver cancers. MYC-driven liver cancer cells are methionine dependent and S-adenosylmethionine (SAM), the predominant methyl donor, partially rescues methionine depletion. A low methionine diet, or the methylation inhibitor 5-azacytidine limited MYC-driven tumor formation, but RAS-driven liver cancer was resistant to a low methionine diet. Metabolic tracing of methionine catabolism in MYC high cells identified increased m5C methylation of genomic DNA or ribosomal RNA. We found NOP2, an rRNA m5C-methyltransferase, was regulated by both MYC and methionine. RNA bisulfite seq demonstrated that methionine depletion reduced methylation levels at 28S rRNA C4099, C3438 and C3683. NOP2 knockdown decreased the methylation at C4099, and slightly affected C3438 methylation, suggesting the involvement of NOP2 in methionine dependence. Depletion of NOP2 selectively inhibited MYC liver cancer cell proliferation, tumorigenesis and in vivo tumor growth. Thus, methionine catabolism is critical for MYC-driven liver tumorigenesis and NOP2 may serve as a new therapeutic target in liver cancer.
2026-01-20 | GSE296765 | GEO
Project description:Hepatocellular carcinoma (HCC) represents the third leading cause of cancer-related death worldwide and has been increasing in recent years in developed nations1,2. The MYC oncogene or its paralogs are frequently amplified or overexpressed in particularly aggressive subtypes of cancer associated with stem cell-like features and worse clinical outcomes3,4, including in liver cancer5. Unfortunately, selective inhibitors that target MYC or its transcriptional program are not yet clinically available for therapy of HCC. Here, we identified methionine metabolism as a selective vulnerability for MYC but not RAS-driven liver cancers. MYC-driven liver cancer cells are methionine dependent and S-adenosylmethionine (SAM), the predominant methyl donor, partially rescues methionine depletion. A low methionine diet, or the methylation inhibitor 5-azacytidine limited MYC-driven tumor formation, but RAS-driven liver cancer was resistant to a low methionine diet. Metabolic tracing of methionine catabolism in MYC high cells identified increased m5C methylation of genomic DNA or ribosomal RNA. We identified NOP2, an rRNA m5C-methyltransferase as a MYC target gene. Knockdown of NOP2 selectively inhibited MYC liver cancer cell proliferation and in vivo tumorigenesis. Thus, methionine catabolism is critical for MYC-driven liver tumorigenesis and NOP2 may serve as a new therapeutic target in liver cancer.
2022-10-06 | GSE214724 | GEO
Project description:Methionine metabolism and NOP2 methyltransferase are essential for MYC-Driven liver tumorigenesis
| PRJNA1261023 | ENA
Project description:Histone modifications are integral to epigenetics through their influence on gene expression and cellular status. While it's established that metabolism, including methionine metabolism, can impact histone methylation, the direct influence of methionine availability on crucial histone marks that determine the epigenomic process remains poorly understood. In this study, we demonstrate that methionine, through its metabolic product, S-adenosylmethionine (SAM), dynamically regulates H3K36me3, a cancer-associated histone modification known to influence cellular status, and myogenic differentiation of mouse myoblast cells. We further demonstrate that the methionine-dependent effects on differentiation are mediated in part through the histone methyltransferase SETD2, which senses methionine levels. Additionally, methionine restriction leads to preferential decreases in H3K36me3 abundance and genome accessibility of genes involved in myogenic differentiation. Importantly, the effects of methionine restriction on differentiation and chromatin accessibility can be phenocopied by the deletion of Setd2. Collectively, this study demonstrates that methionine metabolism through its ability to be sensed by chromatin modifying enzymes can have a direct role in influencing cell fate determination.
2023-11-30 | GSE248198 | GEO
Project description:Histone modifications are integral to epigenetics through their influence on gene expression and cellular status. While it's established that metabolism, including methionine metabolism, can impact histone methylation, the direct influence of methionine availability on crucial histone marks that determine the epigenomic process remains poorly understood. In this study, we demonstrate that methionine, through its metabolic product, S-adenosylmethionine (SAM), dynamically regulates H3K36me3, a cancer-associated histone modification known to influence cellular status, and myogenic differentiation of mouse myoblast cells. We further demonstrate that the methionine-dependent effects on differentiation are mediated in part through the histone methyltransferase SETD2, which senses methionine levels. Additionally, methionine restriction leads to preferential decreases in H3K36me3 abundance and genome accessibility of genes involved in myogenic differentiation. Importantly, the effects of methionine restriction on differentiation and chromatin accessibility can be phenocopied by the deletion of Setd2. Collectively, this study demonstrates that methionine metabolism through its ability to be sensed by chromatin modifying enzymes can have a direct role in influencing cell fate determination.
2023-11-30 | GSE248197 | GEO
Project description:NOP2 is a member of the NOL1/NOP2/SUN structural domain (NSUN) family and is responsible for catalyzing post-transcriptional modification of RNA via 5-methylcytosine (m5C). m5C modification dysregulation has been implicated in the pathogenesis of a variety of malignancies. Here, we investigated the expression of NOP2 in lung cancer tissues and cells and found that its expression was significantly upregulated. This is consistent with previous reports. To further investigate the mechanism by which NOP2 affects lung cancer development, RNA sequence analysis was performed. In conclusion, our study emphasizes the important role of NOP2 in lung cancer, and its promise as a potential target for lung cancer therapy.
2024-06-20 | GSE270282 | GEO
Project description:5-Methylcytosine (m5C) is a base modification broadly found on a variety on coding and non-coding RNAs in the human transcriptome. In eukaryotes m5C is catalyzed by enzymes of the NOL1/NOP2/SUN domain (NSUN) family, which is composed of seven members in humans (NSUN1-7). NOP2/NSUN1, a member of this family, has been mostly characterized in budding yeast as an essential ribosome biogenesis factor required for the deposition of m5C at position C2870 of the 25S rRNA. Although human NOP2/NSUN1 has been known to be an oncogene overexpressed in several types of cancer for decades, its functions remain poorly characterized. To better define the roles of NOP2/NSUN1 in human cells, we used an adapted genome-wide methylation of individual-nucleotide-resolution crosslinking and immunoprecipitation-sequencing (miCLIP-seq) approach to identify its RNA methylation targets. Our analysis revealed that vault RNA 1.2 (vtRNA1.2) and 28S rRNA are NOP2/NSUN1-specific methylated targets. In addition, NOP2/NSUN1 predominantly binds to rRNA, followed by C/D box snoRNA, and other ncRNAs. Together, our data provided a genome-wide spectrum of NOP2/NSUN1 binding RNA and methylated target RNA for understanding the function of human NOP2/NSUN1.
2021-11-15 | GSE188735 | GEO
Project description:MYC interacts with the G9a histone methyltransferase to drive transcriptional repression and tumorigenesis
| PRJNA473533 | ENA
Project description:Targeting altered tumor cell metabolism might provide an attractive opportunity for patients with acute myeloid leukemia (AML). An amino acid dropout screen on primary leukemic stem cells and progenitor populations revealed a number of amino acid dependencies, of which methionine was one of the strongest. By using various metabolite rescue experiments, NMR-based metabolite quantifications and 13C-tracing, polysomal profiling, and ChIP-seq, we identified that methionine is used predominantly for protein translation and to provide methyl groups to histones via S-adenosylmethionine for epigenetic marking. H3K36me3 was consistently the most heavily impacted mark following loss of methionine. Methionine depletion also reduced total RNA levels, enhanced apoptosis and induced a cell cycle block. ROS levels were not increased following methionine depletion and replacement of methionine with glutathione or N-acetylcysteine could not rescue phenotypes, excluding a role for methionine in controlling redox balance control in AML. Although considered to be an essential amino acid, methionine can be recycled from homocysteine. We uncovered that this is primarily performed by the enzyme methionine synthase and only when methionine availability becomes limiting. In vivo, dietary methionine starvation was not only tolerated by mice, but also significantly delayed both cell line and patient-derived AML progression. Finally, we show that inhibition of the H3K36-specific methyltransferase SETD2 phenocopies much of the cytotoxic effects of methionine depletion, providing a more targeted therapeutic approach. In conclusion, we show that methionine depletion is a vulnerability in AML that can be exploited therapeutically, and we provide mechanistic insight into how cells metabolize and recycle methionine.
2022-12-21 | GSE220236 | GEO
Project description:RNF4 sustains Myc-driven tumorigenesis by facilitating DNA replication
2022-08-16 | MSV000090142 | MassIVE