Pyrimidine synthase CAD deamidates and inactivates p53
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1209001 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31956654_1.fastq.gz | Fastqsanger.gz | |||
| SRR31956654_2.fastq.gz | Fastqsanger.gz | |||
| SRR31956655_1.fastq.gz | Fastqsanger.gz | |||
| SRR31956655_2.fastq.gz | Fastqsanger.gz | |||
| SRR31956656_1.fastq.gz | Fastqsanger.gz |
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Project description:p53, a critical tumor suppressor, regulates the cell cycle in response to DNA damage and metabolic changes. While p53 stability and activity are predominantly governed by post-translational modifications, the role of deamidation in modulating p53 function remains unclear. This study demonstrates that 6-diazo-5-oxo-L-norleucine (DON) inhibits CAD, a glutamine amidotransferase, to block p53 deamidation, thereby activating the p53 signaling pathway and suppressing tumor cell proliferation. Metabolomic analyses confirmed that DON inhibits CAD-mediated pyrimidine biosynthesis, but this metabolic disruption is not the primary driver of p53 activation. CAD deamidates p53 at N235 and N239, impairing its transcriptional activity and promoting tumor growth. DON restores p53 function by inhibiting CAD’s deamidase activity. Clinical data revealed elevated CAD expression in tumors with wild-type TP53, correlating with poor patient survival. Our findings uncover a novel mechanism by which CAD suppresses p53 activity via deamidation and propose that DON treatment may benefit cancer patients with wild-type TP53 and high CAD expression.
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Project description:Aerobic glycolysis, which is also termed the Warburg effect, is one of the aberrant metabolic pathways in highly proliferating cells. Glycolysis provides glycolytic metabolites to support the generation of biomass, such as nucleotides, amino acids, and lipids. To date, no studies have explored interrelationships between glycolysis and other metabolic pathways. Phosphofructokinase-2/fructose-2,6-bisphosphatase 3 (PFKFB3) activates glycolysis by synthesizing fructose-2,6-bisphosphate (F2,6BP), which allosterically activates the rate-limiting enzyme 6-phosphofructo-1-kinase (PFK-1). In this study, we found that PFKFB3 directly interacts with and regulates the phosphorylation of carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD), the enzyme catalyzing the first three steps of de novo pyrimidine synthesis. PFKFB3 inactivation reduced de novo pyrimidine synthesis, RNA and DNA production, and the growth of cancer and proliferative cells. Thus, the glycolytic activator PFKFB3 bridges glycolysis with pyrimidine synthesis, unites both glucose metabolism and nucleic acid metabolism, and contributes to cell proliferation under both physiological and pathological conditions.
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Project description:p53 is a crucial tumor suppressor in vertebrates that is frequently mutated in human cancers. Most mutations are missense mutations that render p53 inactive in suppressing tumor initiation and progression. Developing small molecule drugs to convert mutant p53 into an active, wild-type-like conformation is a significant focus for personalized cancer therapy. Prior research indicates that reactivating p53 suppresses cancer cell proliferation and tumor growth in animal models. Early clinical evidence with a compound selectively targeting p53 mutants with substitutions of tyrosine 220 suggests potential therapeutic benefits of reactivating p53 in patients. This study identifies and examines the UCI-1001 compound series as a potential corrector for several p53 mutations. The findings indicate that UCI-1001 treatment in p53 mutant cancer cell lines inhibits growth and reinstates wild-type p53 activities, including DNA binding, target gene activation, and induction of cell death. Cellular thermal shift assays, conformation-specific immunofluorescence staining, and differential scanning fluorometry suggest that UCI-1001 interacts with and alters the conformation of mutant p53 in cancer cells. These initial results identify pyrimidine trione derivatives of the UCI-1001 series as candidates for p53 corrector drug development.
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Project description:TMPRSS2-ERG fusion is the most common genetic alteration in prostate cancer (PCa) and TP53 is the most frequently mutated gene in human cancers. However, their precise roles in PCa pathogenesis remain elusive. Here we showed that TMPRSS2-ERG fusion co-occurred with TP53 deletion/mutation in PCa patient specimens. ERG overexpression and Trp53 knockout/R172H mutant knockin induced pyrimidine synthesis gene (PSG) expression and prostate tumorigenesis in mice. Gain-of-function p53 mutants bound to the CTNNB1 promoter and upregulated β-Catenin. Overexpressed ERG and β-Catenin co-occupied PSG loci and mediated PSG expression, and high PSG expression associated with increased β-Catenin level and poor overall survival of PCa patients. β-Catenin inhibition by proteolysis-targeting chimeras (PROTACs) of its co-activator CBP and partner proteins LEF1/TCFs blocked ERG/p53-mutant PCa growth. Our study identifies CTNNB1 as a transcriptional target of p53 GOF-mutants, and reveals a druggable dependency on β-Catenin and pyrimidine synthesis in p53-mutated cancers with or without TMPRSS2-ERG fusion.
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Project description:TMPRSS2-ERG fusion is the most common genetic alteration in prostate cancer (PCa) and TP53 is the most frequently mutated gene in human cancers. However, their precise roles in PCa pathogenesis remain elusive. Here we showed that TMPRSS2-ERG fusion co-occurred with TP53 deletion/mutation in PCa patient specimens. ERG overexpression and Trp53 knockout/R172H mutant knockin induced pyrimidine synthesis gene (PSG) expression and prostate tumorigenesis in mice. Gain-of-function p53 mutants bound to the CTNNB1 promoter and upregulated β-Catenin. Overexpressed ERG and β-Catenin co-occupied PSG loci and mediated PSG expression, and high PSG expression associated with increased β-Catenin level and poor overall survival of PCa patients. β-Catenin inhibition by proteolysis-targeting chimeras (PROTACs) of its co-activator CBP and partner proteins LEF1/TCFs blocked ERG/p53-mutant PCa growth. Our study identifies CTNNB1 as a transcriptional target of p53 GOF-mutants, and reveals a druggable dependency on β-Catenin and pyrimidine synthesis in p53-mutated cancers with or without TMPRSS2-ERG fusion.
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Project description:Pleural mesothelioma (PM) is one of the deadliest cancers, with limited therapeutic options due to its therapeutically intractable genome, which is characterized by the functional inactivation of tumor suppressor genes (TSGs) and high tumor heterogeneity, including diverse metabolic adaptations. However, the molecular mechanisms underlying these metabolic alterations remain poorly understood, particularly how TSG inactivation rewires tumor metabolism to drive tumorigenesis and create metabolic dependencies. Through integrated multi-omics analysis, we identify for the first time that NF2 loss of function defines a distinct PM subtype characterized by enhanced de novo pyrimidine synthesis, which NF2-deficient PM cells are critically dependent on for sustained proliferation in vitro and in vivo. Mechanistically, NF2 loss activates YAP, a downstream proto-oncogenic transcriptional coactivator in the Hippo signalling pathway, which in turn upregulates CAD and DHODH, key enzymes in the de novo pyrimidine biosynthesis pathway. Our findings provide novel insights into metabolic reprogramming in PM, revealing de novo pyrimidine synthesis as a synthetic lethal vulnerability in NF2-deficient tumors. This work highlights a potential therapeutic strategy for targeting NF2-deficient mesothelioma through metabolic intervention.
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Project description:Metabolic heterogeneity resulting from the intrinsic heterogeneity of human tumors has been shown to cause a myriad of adverse outcomes of tumor therapy, including resistance to chemotherapy, but the mechanisms inside remain largely unknown. Here, we found that the de novo pyrimidine synthesis pathway, which we previously identified as crucial for the proliferation of gastric and colon cancer cells, determines the chemosensitivity of these cancer types. In the chemosensitive cells, chemotherapeutic drugs such as 5-FU promoted the degradation of CAD, an enzyme that is rate-limiting for pyrimidine synthesis, leading to the apoptosis of these cells. We also found that CAD needed to be cleaved, by activated caspase-3 on its Asp1371 residue, before its degradation. Upregulation of CAD, either by overexpression or by a mutation on the Asp1371 to block the caspase-3 cleavage, conferred tumor chemoresistance in both mouse xenograft models and the Cldn18-ATK mouse gastric tumor models. Importantly, mutations related to Asp1371 of CAD were found in gastric tumor samples of patients who underwent unsuccessful neoadjuvant chemotherapy. By searching for a compound that is capable of degradating the CAD-Asp1371 mutant, we discovered that a compound called RMY-186 can be used to treat chemoresistant tumors related to CAD mutations, resulting in a significant improvement in the effectiveness of chemotherapy. We have, therefore, revealed the vulnerability of de novo pyrimidine synthesis during chemotherapy, which can be targeted to overcome chemotherapeutic resistance and augment the antitumor efficacy of genotoxic chemotherapy agents.
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