USF1 promotes urea cycle dysregulation and migration of ccRCC through inhibiting ASS1
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo Sapiens
SUBMITTER: 
Ying Lu
PROVIDER: PXD054571 | iProX | Sat Aug 03 00:00:00 BST 2024
REPOSITORIES: iProX
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Project description:<p>Urea cycle disorders represent a group of rare inborn errors of metabolism that lead to accumulation of ammonia, a toxic product of protein metabolism. Individuals with urea cycle disorders cannot metabolize the ammonia that accumulates due to enzyme deficiency. The symptoms of these disorders may present at birth, childhood or adulthood (milder deficiencies). There are currently eight enzyme deficiencies that constitute the range of inborn errors of ureagenesis. This project will focus on the most common enzyme disorder of the urea cycle, ornithine transcarbamylase deficiency, inherited as an X-linked trait.</p> <p>This project will study cognitive and motor dysfunction in patients who are female carriers of ornithine transcarbamylase deficiency (OTCD) or are males with late onset presentation of OTCD, utilizing state of the art MRI (magnetic resonance imaging), a non -invasive technique. This project seeks to improve our understanding of the underlying neural mechanisms that contribute to metabolic, cognitive, sensory and motor abnormalities in urea cycle disorders, which although individually rare, collectively constitute a major cause of neonatal encephalopathy, leading to significant morbidity and mortality. As a result of this study, a greater understanding of the anatomic, cognitive, motor, and biochemical underpinnings of neurologic damage attributable to this metabolic disorder will be gained. Experimental approaches will combine sensory, cognitive and motor testing with structural, functional and molecular magnetic resonance imaging to study symptomatic and asymptomatic heterozygous female carriers of X-linked ornithine transcarbamylase deficiency (OTCD), and late onset hemizygous males. Participants to be included in the studies will range from ages 18-60 years and will be compared to an age-matched typically developed (TD) comparison group.</p> <p>For our research, we use anatomic MRI, functional Magnetic Resonance Imaging (fMRI), and magnetic resonance spectroscopy (MRS) to monitor brain activity. The technique of fMRI provides detailed maps of the brain areas underlying human mental activities. By using fMRI, we are able to observe how the brain is functioning while a person is performing a specific task, such as reading. We can not only observe differences in the structure of the brain, but can also measure differences in brain function and activity as well. This information will ultimately be used to provide a basis for designing more effective interventions and methods for early identification of learning disabilities in patients with OTCD and related disorders. We will also use MRS to study various brain chemicals such as glutamine using the non-invasive MRI imaging techniques.</p>
| phs001108 | dbGaP
Project description:Metabolic reprogramming is critical for tumor initiation and progression. However, the exact impact of specific metabolic changes on cancer progression is poorly understood. Here, we integrate multimodal analyses of primary and metastatic clonally-related clear cell renal cancer cells (ccRCC) grown in physiological media to identify key stage-specific metabolic vulnerabilities. We show that a VHL loss-dependent reprogramming of branched-chain amino acid catabolism sustains the de novo biosynthesis of aspartate and arginine enabling tumor cells with the flexibility of partitioning the nitrogen of the amino acids depending on their needs. Importantly, we identify the epigenetic reactivation of argininosuccinate synthase (ASS1), a urea cycle enzyme suppressed in primary ccRCC, as a crucial event for metastatic renal cancer cells to acquire the capability to generate arginine, invade in vitro and metastasize in vivo. Overall, our study uncovers a mechanism of metabolic flexibility occurring during ccRCC progression, paving the way for the development of novel stage-specific therapies.
2022-11-10 | GSE217211 | GEO
Project description:The urea cycle is frequently rewired in cancer cells to meet the metabolic demands of cancer, yet our understanding about the regulatory mechanisms for this pathway in different types of cancer is very limited. In this study, we discover that oncogenic activation of KRAS in non-small cell lung cancer (NSCLC) silences the expression of arginosuccinate synthase 1 (ASS1), a urea cycle enzyme catalyzing the production of arginine from aspartate and citrulline, and thereby diverts the utilization of aspartate to pyrimidine synthesis to meet the high demand for DNA replication in KRAS-mutant NSCLC. Specifically, KRAS signaling facilitates a hypo-acetylated state in the promoter region of ASS1 gene in a histone deacetylase 3 (HDAC3)-dependent manner, which in turn impedes the recruitment of the transcription factor c-MYC for ASS1 transcription. ASS1 suppression in KRAS-mutant NSCLC cancer cells impairs the biosynthesis of arginine and renders growth dependency on SLC7A1, an arginine transmembrane transport, to import extracellular arginine. Depletion of SLC7A1 in both patient-derived organoid and xenograft models obtains a substantial therapeutic benefit in inhibiting KRAS-driven NSCLC growth. Together, our findings uncover a new role of oncogenic KRAS in rewiring urea cycle metabolism and identify SLC7A1-mediated arginine uptake as a therapeutic vulnerability in treating KRAS-mutant NSCLC.
2024-01-20 | GSE253688 | GEO
Project description:Urea cycle (UC) dysfunction is linked to both tumorigenesis and poor prognosis in multiple cancers. However, the role of UC metabolism in tumor-stroma crosstalk is unclear. Here, we show that colorectal cancer (CRC) cells induce reprogramming of UC metabolism in cancer-associated fibroblasts (CAFs), which is mediated by CRC-derived exosomes. Reprogrammed CAFs support CRC cell growth by providing UC metabolites, especially arginine (Arg). Consequently, Arg deprivation resulted in growth inhibition of CRC cells. Furthermore, we found that Arg deprivation increases CRC’s dependence on putrescine (Put) and upregulates the expression of the polyamine biosynthetic rate-limiting enzyme ornithine decarboxylase (ODC). Combined Arg deprivation and ODC inhibitor effectively restrains CRC cell growth. Our study illustrates the UC metabolic interaction between CAFs and CRC cells and demonstrates the potential therapeutic utility of Arg restriction and ODC blockade combination treatment for colorectal cancer.
2025-01-31 | GSE285472 | GEO
Project description:Metabolic reprogramming is critical for tumor initiation and progression. However, the exact impact of specific metabolic changes on cancer progression is poorly understood. Here, we integrate multimodal analyses of primary and metastatic clonally-related clear cell renal cancer cells (ccRCC) grown in physiological media to identify key stage-specific metabolic vulnerabilities. We show that a VHL loss-dependent reprogramming of branched-chain amino acid catabolism sustains the de novo biosynthesis of aspartate and arginine enabling tumor cells with the flexibility of partitioning the nitrogen of the amino acids depending on their needs. Importantly, we identify the epigenetic reactivation of argininosuccinate synthase (ASS1), a urea cycle enzyme suppressed in primary ccRCC, as a crucial event for metastatic renal cancer cells to acquire the capability to generate arginine, invade in vitro and metastasize in vivo. Overall, our study uncovers a mechanism of metabolic flexibility occurring during ccRCC progression, paving the way for the development of novel stage-specific therapies.
2022-11-09 | PXD037464 | Pride
Project description:Pulmonary tuberculosis (TB) generates chronic systemic inflammation and metabolic dysregulation. The liver is the master regulator of metabolism and to determine the impact of pulmonary TB on this organ we undertook unbiased mRNA analyses of the liver in mice with TB. Pulmonary TB led to upregulation of genes in the liver related to interferon signalling and glycolysis, and downregulation of genes encoding gluconeogenesis rate-limiting enzyme
2024-09-17 | GSE273691 | GEO
Project description:Urea cycle disorders with hyperammonemia remain difficult to treat and eventually necessitate liver transplantation. An ornithine transcarbamylase defect (Otcspf-ash) mouse model, a model of urea cycle disorder, was used to test whether knockdown of a key glutamine metabolism enzyme glutaminase 2 (Gls2) or glutamine dehydrogenase 1 (Glud1) could rescue the hyperammonemia and associated lethality induced by a high protein diet. Reduced hepatic expression of Gls2, but not Glud1, by AAV8-mediated delivery of a short hairpin RNA in Otcspf-ash mice diminished hyperammonemia, reduced body weight loss, and reduced lethality. These data suggest that Gls2 hepatic knockdown could help alleviate risk for hyperammonemia and other clinical manifestations of patients suffering from defects in the urea cycle.
2022-06-07 | GSE179342 | GEO
Project description:Clear cell renal cell carcinoma (ccRCC) is characterized by its aggressive invasion and metastasis, posing significant clinical challenges. Understanding the molecular mechanisms underlying its progression is crucial for developing effective therapeutic strategies. The role of TRIM21 in regulating ASS1 in ccRCC addresses a critical gap in understanding the molecular mechanisms underlying ccRCC tumorigenesis. This study aims to investigate the role of TRIM21 in ccRCC and elucidate its expression patterns in clinical tissue and its impact on patient prognosis. The Real-time RT-PCR and western blot were used to determine the mRNA and protein expression of TRIM21 in ccRCC, and the TCGA database correlates with patient survival prognosis. Lentivirus-mediated TRIM21 modulation in ACHN, Caki-1, and 786-O cells reveals altered migration and invasion capabilities assessed via Wound Healing and Transwell assays. Metabolomic analysis reveals TRIM21 overexpression in ACHN cells induces metabolic reprogramming impacting urea cycle intermediates arginine, ornithine, and citrulline, elucidated via metabolomic detection kits. Our findings reveal that TRIM21 expression is low in ccRCC, but its high expression impedes cell migration and invasion while ameliorating urea cycle dysregulation by upregulating ASS1. Furthermore, TRIM21 enhances ASS1 protein stability through K63-linked ubiquitination modification. Moreover, clinical studies validating the prognostic value of TRIM21 and ASS1 in ccRCC patients may guide personalized treatment strategies ultimately improving patient outcomes. By investigating this interaction, researchers seek to shed light on potential diagnostic and therapeutic strategies for ccRCC offering valuable insights into its pathogenesis and metabolic reprogramming.
2024-08-13 | PXD054847 |
Project description:Purpose: In this study, we have undertaken the whole proteomic analysis and got a better understanding of biological processes involved in the development and progression of ccRCC. We hope promising biomarkers can be uncovered to facilitate early diagnosis, predict the prognosis and progression, more importantly, to be applied as potential therapeutic targets. Experimental design: Fresh frozen tissue samples were surgically resected from patients with local or locally advanced ccRCC. Trypsin digested proteins were analyzed using TMT-based LC-MS/MS proteomic approach, followed by bioinformatic analysis. A potential prognostic marker FMNL1, annotated with actin cytoskeleton assembly and cell migration, was chosen to be validated in TCGA_KIRC datasets(n=597), further validation sets(n=20) and expanded validation sets(n=97). Results: A total of 657 differentially expressed proteins were identified and quantified between ccRCC and adjacent normal tissues (p-value<0.05, FC>2 or<1/2), of which 186 proteins were up-regulated and 471 proteins were down-regulated. Bioinformatic analysis showed enriched metabolic biological processes and pathways including oxidative phosphorylation, valine, leucine and isoleucine degeneration, propanoate metabolism, fatty-acid degeneration, TCA cycle, glycolysis/gluconeogenesis, etc. Univariate and multivariate analysis defined FMNL1 as an independent negative prognostic marker in the TCGA datasets. High expression of FMNL1 correlated significantly with tumor stage, T stage, lymph node metastasis(P<0.05), and distant metastasis(P<0.05) both in the TCGA-KIRC datasets and expanded validation sets. And KM survival curve illustrated that patients with high FMNL1 protein level had shorter OS time in the expanded validation sets (p=0.0273) Conclusion and clinical relevance: The proteomic results uncovered sophisticated metabolic reprogramming of ccRCC and indicated that the upregulation of rate-limiting enzymes in glycolysis and mitochondrial impairment may be the cause of metabolic reprogramming in ccRCC. Moreover, FMNL1 has been identified as a diagnostic and prognostic marker, and may be implicated in the progression of ccRCC.
2022-02-16 | PXD022919 | Pride
Project description:<p>Metabolic reprogramming is critical for tumor initiation and progression. However, the exact impact of specific metabolic changes on cancer progression is poorly understood. Here, we integrate multimodal analyses of primary and metastatic clonally-related clear cell renal cancer cells (ccRCC) grown in physiological media to identify key stage-specific metabolic vulnerabilities. We show that a VHL loss-dependent reprogramming of branched-chain amino acid catabolism sustains the de novo biosynthesis of aspartate and arginine enabling tumor cells with the flexibility of partitioning the nitrogen of the amino acids depending on their needs. Importantly, we identify the epigenetic reactivation of argininosuccinate synthase (ASS1), a urea cycle enzyme suppressed in primary ccRCC, as a crucial event for metastatic renal cancer cells to acquire the capability to generate arginine, invade in vitro and metastasize in vivo. Overall, our study uncovers a novel mechanism of metabolic flexibility occurring during ccRCC progression, paving the way for the development of novel stage-specific therapies</p>
2022-12-08 | MTBLS5615 | MetaboLights