PHF8-GLUL axis in lipid deposition and tumor growth of clear cell renal cell carcinoma

Science Advances, Journal Year: 2023, Volume and Issue: 9(31)

Published: Aug. 2, 2023

For clear cell renal carcinoma (ccRCC), lipid deposition plays important roles in the development, metastasis, and drug resistance. However, molecular mechanisms underlying ccRCC remain largely unknown. By conducting an unbiased CRISPR-Cas9 screening, we identified epigenetic regulator plant homeodomain finger protein 8 (PHF8) as deposition. Moreover, PHF8 is regulated by von Hippel-Lindau (VHL)/hypoxia-inducible factor (HIF) axis essential for VHL deficiency-induced transcriptionally up-regulates glutamate-ammonia ligase (GLUL), which promotes progression. Mechanistically, forming a complex with c-MYC, TEA domain transcription 1 (TEAD1) histone demethylation-dependent manner. Subsequently, TEAD1 GLUL transcriptionally. Pharmacological inhibition of l-methionine sulfoximine not only repressed tumor growth but also enhanced anticancer effects everolimus. Thus, PHF8-GLUL represents potential therapeutic target treatment.

Language: Английский

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Metabolic Reprogramming in Cancer: Implications for Immunosuppressive Microenvironment

Immunology, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 27, 2024

ABSTRACT Cancer is a complex and heterogeneous disease characterised by uncontrolled cell growth proliferation. One hallmark of cancer cells their ability to undergo metabolic reprogramming, which allows them sustain rapid survival. This reprogramming creates an immunosuppressive microenvironment that facilitates tumour progression evasion the immune system. In this article, we review mechanisms underlying in discuss how these alterations contribute establishment microenvironment. We also explore potential therapeutic strategies targeting vulnerabilities enhance immune‐mediated anti‐tumour responses. Trial Registration ClinicalTrials.gov identifier: NCT02044861, NCT03163667, NCT04265534, NCT02071927, NCT02903914, NCT03314935, NCT03361228, NCT03048500, NCT03311308, NCT03800602, NCT04414540, NCT02771626, NCT03994744, NCT03229278, NCT04899921

Language: Английский

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Omics Analyses of Intestinal Microbiota and Hypothalamus Clock Genes in Circadian Disturbance Model Mice Fed with Green Tea Polyphenols

Journal of Agricultural and Food Chemistry, Journal Year: 2022, Volume and Issue: 70(6), P. 1890 - 1901

Published: Feb. 3, 2022

Green tea polyphenols (GTP) have similar activities as prebiotics, which effectively regulate the structure of intestinal flora and affect their metabolic pathways. The is closely related to host's circadian rhythm, supplementation with GTP may be an effective way improve rhythm disorders. In this study, we established a mouse model disturbance anthropogenic investigate regulation mechanism on host rhythms. After 4 weeks administration, results showed that significantly alleviated structural disorder microbiota, thus regulating metabolites associated brain nerves Moreover, single-cell transcription hypothalamus suggested up-regulated number astrocytes oligodendrocytes adjusted expression core clock genes Csnk1d, Clock, Per3, Cry2, BhIhe41 caused by disruption. Therefore, study provided evidence can physiological health hosts positively affecting gene expression.

Language: Английский

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The Role of Glutamine Synthetase on the Sensitivity to Radiotherapy of Hepatocellular Carcinoma

Radiation Research, Journal Year: 2025, Volume and Issue: 203(3)

Published: Feb. 4, 2025

The objective of this study was to investigate the relationship between radiotherapy sensitivity, glutamine synthetase (GS), and oxidative stress (OS) in human hepatocellular carcinoma (HCC) cells. HCC cells were X-ray irradiated, effect inhibition on proliferative capacity examined using CCK-8 colony formation assay. Real-time quantitative PCR assays used detect L-methionine sulfoximine (MSO) cellular expression levels efficiency knockdown HepG2 Glutamine activity assay kit viability tissues. Oxidative production assayed an kit. Subcutaneous xenografts effects radiation tumor growth vivo. results showed that apparent cell proliferation after significantly reduced radiotherapy, which closely related increased radiotherapy. Furthermore, animal experiments also combination induced a stronger suppressive could act as radiosensitizer

Language: Английский

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High-ammonia microenvironment promotes stemness and metastatic potential in hepatocellular carcinoma through metabolic reprogramming

Discover Oncology, Journal Year: 2025, Volume and Issue: 16(1)

Published: Feb. 14, 2025

Hepatocellular carcinoma (HCC) is a prevalent and aggressive form of liver cancer, characterized by frequent recurrence metastasis, which remain significant obstacles to effective treatment. Ammonia accumulates in the tumor microenvironment HCC due dysfunction urea cycle, but detailed impact ammonia on cells remains insufficiently understood. We exposed cell lines high concentrations ammonium chloride evaluate alterations proliferation, stemness, migratory potential. After removal, changes cellular behavior were assessed using colony formation, spheroid assays. Transcriptomic metabolomic analyses conducted investigate ammonia-induced metabolic reprogramming gene expression. Additionally, animal models employed validate growth metastasis. Exposure high-ammonia conditions transiently suppressed proliferation without inducing apoptosis. However, following demonstrated increased enhanced elevated capacity. analysis revealed upregulation genes associated with adhesion, migration, glycolysis. Concurrently, profiling indicated lactate production, facilitating after withdrawal. Animal experiments confirmed that exposure accelerated exerts dual effect progression: it initially suppresses later promotes metastasis through reprogramming. Targeting metabolism or glycolysis may represent promising therapeutic strategy for mitigating Future studies utilizing clinical samples are required these findings identify potential strategies targeting metabolism.

Language: Английский

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