The phospholipid transporter PITPNC1 links KRAS to MYC to prevent autophagy in lung and pancreatic cancer
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA847549 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR19595360_1.fastq.gz | Fastqsanger.gz | |||
| SRR19595360_2.fastq.gz | Fastqsanger.gz | |||
| SRR19595361_1.fastq.gz | Fastqsanger.gz | |||
| SRR19595361_2.fastq.gz | Fastqsanger.gz | |||
| SRR19595362_1.fastq.gz | Fastqsanger.gz |
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Project description:Oncogenic KRAS mutations are a key driver for initiation and progression in non-small-cell lung cancer (NSCLC). However, how post-translational modifications (PTMs) of KRAS, especially methylation, modify KRAS activity remain largely unclear. Here, we show that SET domain containing histone lysine methyltransferase 7 (SETD7) interacts with KRAS and methylates KRAS at lysines 182 and 184. SETD7-mediated methylation of KRAS leads to degradation of KRAS and attenuation of the RAS/MEK/ERK signaling cascade, endowing SETD7 with a potent tumor-suppressive role in NSCLC, both in vitro and in vivo. Mechanistically, RABGEF1, a ubiquitin E3 ligase of KRAS, was recruited and promoted KRAS degradation in a K182/K184 methylation-dependent manner. Notably, SETD7 is inversely correlated with KRAS at the protein level in clinical NSCLC tissues. Low SETD7 or RABGEF1 expression is associated with poor prognosis in lung adenocarcinoma patients. Altogether, our results elucidate a tumor-suppressive function of SETD7 that operates via modulating KRAS methylation and degradation.
2023-07-19 | PXD043931 |
Project description:S-adenosylmethionine (SAM) is the methyl donor for biological methylation modifications that regulate protein and nucleic acid functions. Here we show that methylation of a phospholipid, phosphatidylethanolamine (PE), is the major consumer of SAM in budding yeast. The induction of phospholipid biosynthetic genes is accompanied by induction of the enzyme that hydrolyzes S-adenosylhomocysteine (SAH), a product and inhibitor of methyltransferases. Beyond its function for the synthesis of phosphatidylcholine (PC), the methylation of PE facilitates the turnover of SAM for the synthesis of cysteine and glutathione. Strikingly, cells that lack PE methylation accumulate SAM, which leads to hypermethylation of histones and the major phosphatase PP2A, dependency on cysteine, and sensitivity to oxidative stress. Without PE methylation, particular sites on histones then become methyl sinks to enable the turnover of SAM. These findings reveal an unforeseen metabolic function for phospholipid and histone methylation intrinsic to the life of a cell.
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Project description:Phospholipid and nucleotide syntheses are fundamental metabolic processes in eukaryotic organisms, with their dysregulation implicated in various disease states. However, the interplay between these pathways remains elusive. With genetic and metabolic analyses in the yeast S. cerevisiae, we elucidate how cytidine triphosphate utilization and recycling in the Kennedy pathway for phospholipid synthesis influence nucleotide metabolism and redox balance. Deficiencies in the Kennedy pathway impose constraints on nucleotide salvage, prompting compensatory co-activation of de novo nucleotide synthesis and the pentose phosphate pathway. Consequently, this metabolic shift towards alternative nucleotide and phospholipid synthesis pathways fosters the production of antioxidants such as NADPH and glutathione. Additionally, we observe that this oxidation-responsive Kennedy pathway for phospholipid synthesis is inhibited during replicative aging, highlighting its activation as an antioxidative defense mechanism in aged cells. These findings underscore the critical role of pathway choice in phospholipid synthesis in the integrative regulation of nucleotide metabolism, redox balance, and membrane biophysical properties for cellular defense.
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