Methionine oxidation of PKM2 promotes pancreatic cancer metastasis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA743050 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15015592_1.fastq.gz | Fastqsanger.gz | |||
| SRR15015592_2.fastq.gz | Fastqsanger.gz | |||
| SRR15015593_1.fastq.gz | Fastqsanger.gz | |||
| SRR15015593_2.fastq.gz | Fastqsanger.gz | |||
| SRR15015594_1.fastq.gz | Fastqsanger.gz |
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Project description:Hepatocellular carcinoma (HCC) is notorious for its early and frequent metastases. To understand the molecular mechanisms underlying HCC metastasis, we generated a pulmonary metastasis HCC mouse model and performed both time-series transcriptomics and proteomics analysis of protein methylation. We found that methyltransferase NSD2 with significant upregulation in the tipping point for metastasis was closely correlated with high numbers of methylated-proteins in HCC tissues. NSD2 promoted the invasion and metastasis of HCC cells, both in vitro and in vivo. Mechanistically, NSD2 directly bound to PKM2, a glycolysis rate-limiting enzyme, and catalyzed di-methylation of PKM2 at the lysine 336 residue. Further investigation demonstrated that NSD2-mediated di-methylation of PKM2 increased the intracellular glycolytic rate and lactate production by enhancing its pyruvate kinase activity. High-lactate level in HCC cells lead to lactylation of splicing factor 3B subunit 1 (SF3B1) at lysine 333 residue, promoting SF3B1-mediated RNA splicing of several metastasis-related genes. Further, UNC8153, a novel NSD2-targeted degrader, inhibited HCC metastasis in PDX model. Altogether, our study identifies a key methyltransferase NSD2 for HCC metastasis and reveals a protein methylation-mediated molecular mechanism catalyzed by NSD2 integrate glycolysis regulation and alternative splicing.
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2025-09-30 | PXD056688 | Pride
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2025-09-29 | PXD056689 | Pride
Project description:Hepatocellular carcinoma (HCC) is notorious for its early and frequent metastases. To understand the molecular mechanisms underlying HCC metastasis, we generated a pulmonary metastasis HCC mouse model and performed both time-series transcriptomics and proteomics analysis of protein methylation. We found that methyltransferase NSD2 with significant upregulation in the tipping point for metastasis was closely correlated with high numbers of methylated-proteins in HCC tissues. NSD2 promoted the invasion and metastasis of HCC cells, both in vitro and in vivo. Mechanistically, NSD2 directly bound to PKM2, a glycolysis rate-limiting enzyme, and catalyzed di-methylation of PKM2 at the lysine 336 residue. Further investigation demonstrated that NSD2-mediated di-methylation of PKM2 increased the intracellular glycolytic rate and lactate production by enhancing its pyruvate kinase activity. High-lactate level in HCC cells lead to lactylation of splicing factor 3B subunit 1 (SF3B1) at lysine 333 residue, promoting SF3B1-mediated RNA splicing of several metastasis-related genes. Further, UNC8153, a novel NSD2-targeted degrader, inhibited HCC metastasis in PDX model. Altogether, our study identifies a key methyltransferase NSD2 for HCC metastasis and reveals a protein methylation-mediated molecular mechanism catalyzed by NSD2 integrate glycolysis regulation and alternative splicing.
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Project description:The oxidation of methionine side chains has emerged as an important posttranslational modification of proteins. A diverse array of low-throughput and targeted studies have suggested that the oxidation of methionine residues in select proteins can have diverse impacts on cell physiology, ranging from detrimental effects on protein structure and stability to functional roles in cell signaling. Despite its importance, the large-scale investigation of methionine oxidation in a complex matrix, such as the cellular proteome has been historically hampered by technical limitations. Herein we report a methodology, Methionine Oxidation by Blocking (MobB), that allows for accurate and precise quantification of low levels of methionine oxidation typically observed in vivo. To demonstrate the utility of this methodology, we applied MobB to the brain tissues of young (6 m.o.) and old (20 m.o.) mice and identified over 280 novel sites for in vivo methionine oxidation. We further demonstrated that oxidation stoichiometries for specific methionine residues are highly consistent between individual animals and methionine sulfoxides are enriched in clusters of functionally related gene products including membrane and extracellular proteins. However, we did not detect significant changes in methionine oxidation in brains of old mice, suggesting that oxidation levels are highly regulated during the course of aging.
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Project description:Alternative splicing of the Pkm gene product generates the PKM1 and PKM2 isoforms of pyruvate kinase, and PKM2 expression is closely linked to embryogenesis, tissue regeneration, and cancer. To interrogate the functional requirement for PKM2 during development and tissue homeostasis, we generated germline PKM2 null mice (Pkm2-/-). Unexpectedly, despite being the primary isoform expressed in most wild-type adult tissues, we found that Pkm2-/- mice are viable and fertile. Thus, PKM2 is not required for embryonic or postnatal development. Loss of PKM2 leads to compensatory expression of PKM1 in the tissues that normally express PKM2. Strikingly, PKM2 loss leads to spontaneous development of hepatocellular carcinoma (HCC) with high penetrance that is accompanied by progressive changes in systemic metabolism characterized by altered systemic glucose homeostasis, inflammation, and hepatic steatosis. Therefore, in addition to its role in cancer metabolism, PKM2 plays a role in controlling systemic metabolic homeostasis and inflammation, thereby preventing HCC by a non-cell-autonomous mechanism. RNA was isolated from flash frozen ground whole liver tissue of 35 week old PKM2 KO and WT mice. Three independent mice from each condition were used as biological replicates.
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