Targeting MYC induces lipid droplet accumulation by upregulation of HILPDA in clear cell renal cell carcinoma
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ABSTRACT:
PROVIDER: PRJNA924799 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23100031_1.fastq.gz | Fastqsanger.gz | |||
| SRR23100031_2.fastq.gz | Fastqsanger.gz | |||
| SRR23100032_1.fastq.gz | Fastqsanger.gz | |||
| SRR23100032_2.fastq.gz | Fastqsanger.gz | |||
| SRR23100033_1.fastq.gz | Fastqsanger.gz |
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Project description:Metabolic reprogramming is critical during clear cell renal cell carcinoma (ccRCC) tumorigenesis, manifested by accumulation of lipid droplets (LDs), organelles that have emerged as new hallmarks of cancer. Yet, regulation of their biogenesis is still poorly understood. Here, we demonstrate that MYC inhibition in ccRCC cells lacking the von Hippel Lindau (VHL) gene leads to increased triglyceride content potentiating LD formation in a glutamine-dependent manner. Notably, LD accumulation is prevented, and tumor burden reduced in vivo upon concurrent inhibition of MYC signaling and glutamine metabolism. Furthermore, we identified the hypoxia inducible lipid droplet associated protein (HILPDA) as the key driver for induction of MYC-driven LD accumulation and demonstrated that conversely, proliferation, LD formation, and tumor growth are impaired upon its downregulation. Finally, analysis of ccRCC tissue as well as healthy renal control samples, postulated HILPDA as a specific ccRCC biomarker. Together, these discoveries provide an attractive approach for development of new therapeutic interventions for the treatment of this type of renal cancer.
2024-01-27 | GSE223069 | GEO
Project description:Metabolic reprogramming is critical during clear cell renal cell carcinoma (ccRCC) tumorigenesis, manifested by accumulation of lipid droplets (LDs), organelles that have emerged as new hallmarks of cancer. Yet, regulation of their biogenesis is still poorly understood. Here, we demonstrate that MYC inhibition in ccRCC cells lacking the von Hippel Lindau (VHL) gene leads to increased triglyceride content potentiating LD formation in a glutamine-dependent manner. Importantly, the concurrent inhibition of MYC signaling and glutamine metabolism prevented LD accumulation and reduced tumor burden in vivo. Furthermore, we identified the hypoxia-inducible lipid droplet-associated protein (HILPDA) as the key driver for induction of MYC-driven LD accumulation and demonstrated that conversely, proliferation, LD formation, and tumor growth are impaired upon its downregulation. Finally, analysis of ccRCC tissue as well as healthy renal control samples postulated HILPDA as a specific ccRCC biomarker. Together, these results provide an attractive approach for development of alternative therapeutic interventions for the treatment of this type of renal cancer.
| S-EPMC10873620 | biostudies-literature
Project description:BackgroundLipid droplet formation is a prominent histological feature in clear cell renal cell carcinoma (ccRCC), but the significance and mechanisms underlying lipid droplet accumulation remain unclear.MethodsExpression and clinical significance of MT1G in ccRCC were analyzed by using TCGA data, GEO data and scRNASeq data. MT1G overexpression or knockdown ccRCC cell lines were constructed and in situ ccRCC model, lung metastasis assay, metabolomics and lipid droplets staining were performed to explore the role of MT1G on lipid droplet accumulation in ccRCC.ResultsInitially, we observed low MT1G expression in ccRCC tissues, whereas high MT1G expression correlated with advanced disease stage and poorer prognosis. Elevated MT1G expression promoted ccRCC growth and metastasis both in vitro and in vivo. Mechanistically, MT1G significantly suppressed acylcarnitine levels and downstream tricarboxylic acid (TCA) cycle activity, resulting in increased fatty acid and lipid accumulation without affecting cholesterol metabolism. Notably, MT1G inhibited H3K14 trimethylation (H3K14me3) modification. Under these conditions, MT1G-mediated H3K14me3 was recruited to the CPT1B promoter through direct interaction with specific promoter regions, leading to reduced CPT1B transcription and translation.ConclusionsOur study unveils a novel mechanism of lipid droplet accumulation in ccRCC, where MT1G inhibits CPT1B expression through modulation of H3K14 trimethylation, consequently enhancing lipid droplet accumulation and promoting ccRCC progression. Graphical abstract figure Schematic diagram illustrating MT1G/H3K14me3/CPT1B-mediated lipid droplet accumulation promoted ccRCC progression via FAO inhibition.
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Project description:Senescent glia link neuronal mitochondrial dysfunction and lipid droplet accumulation with age
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Project description:Fatty liver is a condition of excessive triglyceride accumulation in hepatocytes. Additionally, hepatocytes showed a high degree of fat droplet accumulation during excessive alcohol consumption and metabolic syndrome. However, the molecular mechanisms involved in fat droplet formation remain unknown. This study used an in vitro fatty liver formation model of the human liver cancer cell line HepG2 to comprehensively search for fat droplet formation-related genes whose expression changes during fat droplet formation. Microarray analysis with extracted total RNA determined the genes that are involved in fat droplet formation and confirmed their expression by real-time polymerase chain reaction after culturing HepG2 cells in a culture medium containing 0, 50, 200, and 500 μM of oleic acid for 24 h. The results revealed 142 genes demonstrating increased expressions by >2.0 fold with oleic acid treatment and 426 genes demonstrating decreased expressions. Perilipin 2 (PLIN2) was estimated as the gene most closely associated with fatty liver. Lipid droplet formation in HepG2 upregulated PLIN2 in an oleic acid-treated concentration-dependent manner. These results indicate the involvement of genes in oleate treatment-induced lipid droplet formation in HepG2, particularly PLIN2 may play an important role.
2023-12-01 | GSE248166 | GEO
Project description:BackgroundClear cell renal cell carcinoma (ccRCC), the predominant subtype of kidney cancer, possesses characteristic alterations to multiple metabolic pathways, including the accumulation of cytosolic lipid droplets. However, the pathways that drive lipid droplet accumulation in ccRCC cells and their importance to cancer biology remain poorly understood.MethodsWe sought to identify the carbon sources necessary for lipid droplet accumulation using Oil red O staining and isotope-tracing lipidomics. The role of the acyl-CoA synthetase (ACSL) family members, an important group of lipid metabolic enzymes, was investigated using siRNA and drug mediated inhibition. CTB and XTT assays were performed to determine the effect of ACSL3 knockdown and lipid starvation on ccRCC cell viability and shRNA was used to study the effect of ACSL3 in an orthotopic mouse model. The relationship between ferroptosis susceptibility of ccRCC and ACSL3 controlled lipid metabolism was examined using CTB and FACS-based assays. The importance of 5-LOX in ferroptosis susceptibility in ccRCC was shown with XTT survival assays, and the expression level and predictive value of 5-LOX in TCGA ccRCC data was assessed.ResultsWe found that ccRCC cells obtain the necessary substrates for lipid droplet accumulation by metabolizing exogenous serum derived lipids and not through de novo lipogenesis. We show that this metabolism of exogenous fatty acids into lipid droplets requires the enzyme acyl-CoA synthetase 3 (ACSL3) and not other ACSL family proteins. Importantly, genetic or pharmacologic suppression of ACSL3 is cytotoxic to ccRCC cells in vitro and causes a reduction of tumor weight in an orthotopic mouse model. Conversely, ACSL3 inhibition decreases the susceptibility of ccRCC cells to ferroptosis, a non-apoptotic form of cell death involving lipid peroxidation. The sensitivity of ccRCC to ferroptosis is also highly dependent on the composition of exogenous fatty acids and on 5-lipoxygenase (5-LOX), a leukotriene producing enzyme which produces lipid peroxides that have been implicated in other cancers but not in ccRCC.ConclusionsACSL3 regulates the accumulation of lipid droplets in ccRCC and is essential for tumor growth. In addition, ACSL3 also modulates ferroptosis sensitivity in a manner dependent on the composition of exogenous fatty acids. Both functions of ACSL3 could be exploited for ccRCC therapy.
| S-EPMC9528056 | biostudies-literature
Project description:RNA-binding proteins are critical for RNA processing and aberrantly expressed in colorectal cancer (CRC). In this study, by screening and bioinformatic analyses of the TCGA database and GSE20916 and GSE18105 datasets, NCBP2 was ultimately identified as a potential oncogene in CRC. We observed that NCBP2 was overexpressed in tumour tissues; its overexpression was correlated with CRC invasion and distant metastasis and indicated poorer survival in CRC patients. NCBP2 overexpression promoted the proliferation, migration and invasion of CRC cells in vitro and in vivo. Mechanistically, the NCBP2 protein stabilizes LIPG mRNA and increases LIPG expression via direct binding to m7G in the 5’-cap structure of LIPG mRNA. NCBP2 also facilitates lipid droplet accumulation in CRC cells in a LIPG-dependent manner. This study demonstrated that the NCBP2–LIPG–lipid droplet axis represents a new mechanism for CRC growth and distant metastasis and is a promising target for CRC treatment.
2024-08-30 | GSE270402 | GEO
Project description:Senescent glia link neuronal mitochondrial dysfunction and lipid droplet accumulation with age [19082_28_MASTER]
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Project description:Excessive lipid droplet accumulation in hepatocytes drives the progression of metabolic dysfunction-associated steatotic liver disease (MASLD), often leading to inflammation and fibrosis. As obesity and metabolic syndrome rise, MASLD has become a global concern, spurring research into effective treatments. Here, we present the design of a Lipid droplet inhibitor (LDI), incorporating ultra-large mesoporous silica nanostructures along with PKCα C1A and Candida Rugosa lipase, aimed at directly degrading lipid droplets. Through its dual-functional design, this nanostructure captures diacylglycerol using PKCα C1A while hydrolyzing triacylglycerol into smaller molecular fragments via the lipase. Notably, the amphiphilic biomolecules in LDI facilitate the formation of a Pickering emulsion, ensuring stable localization at the lipid-water interface for efficient interaction with lipid droplets. LDI reduced lipid droplet formation and growth in HepG2 cells. In a high-fat diet-induced MASLD model, it alleviated liver pathology and, lowered injury scores by up to 84%. Furthermore, lipidomic analysis confirmed that LDI effectively modulated the hepatic lipid profile, suggesting its potential as a nanoplatform for counteracting lipid droplet accumulation.
2025-07-17 | MTBLS12359 | MetaboLights
Project description:Clear cell renal cell carcinoma (ccRCC), which accounts for the majority of kidney cancer, is known to accumulate excess cholesterol. However, the mechanism and functional significance of the lipid accumulation for development of the cancer remains obscure. In this study, we analyzed 42 primary ccRCC samples, and determined that cholesterol levels of ~ 70% of the tumors were at least two-fold higher than that of benign kidney tissues. Compared to tumors without cholesterol accumulation, those containing excess cholesterol expressed higher levels of scavenger receptor BI (SR-B1), a receptor for uptake of HDL-associated cholesterol, but not genes involved in cholesterol synthesis and uptake of LDL-associated cholesterol. To further determine the roles of sterol accumulation for cancer development, we implanted ccRCC from patients into mouse kidneys using a mouse ccRCC xenograft model. Feeding mice with probucol, a compound lowing HDL-cholesterol, markedly reduced levels of cholesterol in tumors containing excess cholesterol. This treatment, however, did not affect growth of these tumors. Our study suggests that cholesterol overaccumulation in ccRCC is the consequence of increased uptake of HDL-cholesterol as a result of SR-B1 overexpression, but the lipid accumulation by itself may not play a significant role in progression of the cancer.
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