Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

In vivo CRISPR activation screen identifies a lipid metabolism regulator as a driver of bone metastasis

ABSTRACT: The role of lipid metabolism in bone metastasis has not been documented. Here, by using an in vivo CRISPR activation screening system coupled with positive selection, we identify acyl-CoA binding protein (ACBP) as a previously undescribed bone metastasis driver. In non-metastatic cancer cells, overexpression of wild-type ACBP, but not the acyl-CoA binding deficient mutant, stimulates fatty acid oxidation (FAO) and bone metastasis. Conversely, knockout of ACBP in highly bone-metastatic cells abrogates metastatic bone colonization. Mechanistically, ACBP-mediated FAO boosts ATP and NADPH production, reduces reactive oxygen species, and inhibits lipid peroxidation and ferroptosis. ACBP expression correlates with metabolic signaling, bone-metastatic ability, and poor clinical outcomes. Notably, FAO blockade or treatment with a ferroptosis inducer inhibits bone metastasis. Altogether, our findings reveal the role of lipid metabolism in tumor cell adaptation and thriving in the bone, and suggests that agents that target FAO or induce ferroptosis hold potential as bone metastasis drugs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE250240 | GEO | 2025/05/07

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

ACSL4 mediated H3K9 and H3K27 hyperacetylation upregulates SNAIL to drive TNBC metastasis

Project description:Triple-Negative Breast Cancer (TNBC) has profound unmet medical need globally for its devastating clinical outcome associated with rapid metastasis and lack of targeted therapies. Recently, lipid metabolic reprogramming especially fatty acid oxidation (FAO) has emerged as a major driver of breast cancer metastasis. Analyzing the expression of major FAO regulatory genes in breast cancer, we found selective overexpression of acyl-CoA synthetase 4 (ACSL4) in TNBC, which is primarily attributed by the absence of progesterone receptor (PR). Loss of ACSL4 function, by genetic ablation or pharmacological inhibition significantly reduces metastatic potential of TNBC. Global transcriptome analysis reveals that ACSL4 activity positively influences the gene expression related to TNBC migration and invasion. Mechanistically, ACSL4 modulates FAO and intracellular acetyl-CoA levels, leading to hyper-acetylation of particularly H3K9ac and H3K27ac marks resulting in overexpression of SNAIL during the course of TNBC metastatic spread to lymph node and lung. Further, human TNBC metastasis exhibits positive correlation among ACSL4, H3K9ac, H3K27ac, and SNAIL expression. Altogether, our findings provide new molecular insights regarding the intricate interplay between metabolic alterations and epigenetic modifications, intertwined to orchestrate TNBC metastasis and posit a rational understanding for the development of ACSL4 inhibitors as a targeted therapy against TNBC.

2024-12-20 | GSE283282 | GEO

Ferroptotic cell death triggered by conjugated linolenic acids is mediated by ACSL1

Project description:Ferroptosis is associated with lipid hydroperoxides generated by oxidation of polyunsaturated acyl chains. Lipid hydroperoxides are reduced by glutathione peroxidase 4 (GPX4) and GPX4 inhibitors induce ferroptosis. However, the therapeutic potential of triggering ferroptosis in cancer cells with polyunsaturated fatty acids is unknown. We identified conjugated linoleates including α-eleostearic acid (αESA) as novel ferroptosis inducers. αESA did not alter GPX4 activity but was incorporated into cellular lipids and promoted lipid peroxidation and cell death in diverse cancer cell types. αESA-triggered death was mediated by acyl-CoA synthetase long-chain isoform 1, which promoted αESA incorporation into neutral lipids including triacylglycerols. Interfering with triacylglycerol biosynthesis suppressed ferroptosis triggered by αESA but not by GPX4 inhibition. Orally administered tung oil, naturally rich in αESA, limited tumor growth and metastasis with transcriptional changes consistent with ferroptosis. Overall, these findings illuminate a novel approach to ferroptosis, complementary to GPX4 inhibition, with therapeutic potential.

2021-02-08 | GSE162069 | GEO

DNA G-quadruplex structure participates in regulation of lipid metabolism through Acyl-CoA binding protein

Project description:G-quadruplex structure (G4) is a type of DNA secondary structure that widely exists in the genomes of many organisms. G4s are believed to participate in multiple biological processes. Acyl- CoA binding protein (ACBP), a ubiquitously expressed and highly conserved protein in eukaryotic cells, plays important roles in lipid metabolism by transporting and protecting acyl-CoA esters. Here, we report the functional identification of a G4 in the promoter of the ACBP gene in silkworm and human cancer cells. We found that G4 exists as a conserved element in the promoters of ACBP genes in invertebrates and vertebrates. The BmACBP G4 bound with G4-binding protein LARK regulated BmACBP transcription, which was blocked by the G4 stabilizer pyridostatin (PDS) and G4 antisense oligonucleotides. PDS treatment with 5 th instar silkworm larvae decreased the BmACBP expression and triacylglycerides (TAG) level, resulting in reductions in fat body mass, body size and weight and growth and metamorphic rates. PDS treatment and knocking out of the HsACBP G4 in human hepatic adenocarcinoma HepG2 cells inhibited the expression of HsACBP and decreased the TAG level and cell proliferation. Altogether, our findings suggest that G4 of the ACBP genes is involved in regulation of lipid metabolism processes in invertebrates and vertebrates.

2022-05-04 | GSE201939 | GEO

Response of Arabidopsis thaliana seedlings to acyl-CoAs

Project description:Floodings already have a nearly 60% share in the worldwide damage to crops provoked by natural disasters. Climate change will cause plants to be even more frequently exposed to oxygen limiting conditions (hypoxia) in the near future due to heavy precipitation and concomitant waterlogging or flooding events in large areas of the world. Although the homeostatic regulation of adaptive responses to low oxygen stress in plants is well described, it remained unknown by which initial trigger the molecular response to low-oxygen stress is activated. Here, we show that a hypoxia-induced decline of the ATP level of the cell reduces LONG-CHAIN ACYL-COA SYNTHETASE (LACS) activity, which leads to a shift in the composition of the acyl-CoA pool. High oleoyl-CoA levels release the transcription factor RELATED TO APETALA 2.12 (RAP2.12) from its interaction partner ACYL-COA BINDING PROTEIN (ACBP) at the plasma membrane to induce low oxygen-specific gene expression. We show that different acyl-CoAs provoke unique molecular responses revealing a novel role as cellular signalling component also in plants. In terms of hypoxia signalling, dynamic acyl-CoA levels integrate the cellular energy status into the oxygen signalling cascade with ACBP and RAP2.12 being the central hub. The conserved nature of the ACBP:RAP2.12 module in crops and the novel mechanistic understanding of how low-oxygen stress responses are initiated by oleoyl-CoA in plants provide useful leads for enhancing future food security.

2018-04-30 | GSE97186 | GEO

ACBP in brown adipose tissue acts as a negative regulator of adaptive thermogenesis

Project description:The defective activity of brown adipose tissue (BAT) is linked to obesity and cardiometabolic diseases. While there is extensive knowledge about the biological signals that trigger BAT thermogenesis, information regarding active repressors that may contribute to the pathological impairment of BAT function is quite limited. Acyl CoA-Binding Protein (ACBP), also known as Diazepam Binding Inhibitor (DBI), is a protein with intracellular functions related to lipid metabolism. It can also be secreted and act as a circulating regulatory factor that affects multiple tissues and organs. We discovered that ACBP expression and release in BAT are suppressed by noradrenergic, cAMP-dependent signals that stimulate thermogenesis. This regulation occurs through mechanisms involving gene expression and autophagy-related processes. Mice with targeted ablation of the Acbp gene in brown adipocytes exhibit enhanced BAT thermogenic activity and protection against obesity and glucose intolerance induced by a high-fat diet. This is associated with a remodeling of the BAT transcriptome, characterized by the induction of genes related to BAT thermogenesis. Treatment of brown adipocytes with exogenous ACBP suppressed oxidative activity, lipolysis, and the expression of genes associated with thermogenesis. ACBP inhibits the noradrenergic-induced phosphorylation of p38 MAP kinase and CREB, major intracellular mediators of brown adipocyte thermogenesis. Our findings identify the ACBP system as a crucial auto-regulatory repressor of BAT thermogenesis, which responds reciprocally to the noradrenergic induction of BAT activity.

2025-05-08 | GSE285403 | GEO

Tumor metastasis to lymph node requires YAP-dependent metabolic adaptation

Project description:In cancer patients, metastasis of tumors to sentinel lymph nodes (LN) predicts disease progression and often guides treatment decisions. The mechanisms underlying tumor LN metastasis are poorly understood. Using comparative transcriptomics and metabolomics analyses of primary and LN metastatic tumors in mice, we found that LN metastasis requires that tumor cells undergo a metabolic shift toward fatty acid oxidation (FAO). Transcriptional co-activator yes-associated protein (YAP) is selectively activated in LN metastatic tumors, leading to upregulation of genes in the FAO signaling pathway. Pharmacological inhibition of FAO or genetic ablation of YAP suppressed LN metastasis in mice. Several bioactive bile acids were highly accumulated in the LN metastatic tumor. Inhibition of FAO or YAP may merit exploration as therapeutic strategies for mitigating tumor LN metastasis.

2019-02-09 | E-MTAB-7621 | biostudies-arrayexpress

Skeletal muscle mRNA expression in 25 mice with or without genetic defects of mitochondrial fatty acid oxidation (Acadl and Acadvl knockout) using RNA sequencing.

Project description:A mitochondrial long-chain fatty acid oxidation defect leads to dysregulation of plasma long-chain acyl carnitines, dysregulation of plasma amino acids, and an increased reliance on glucocorticoid signaling to maintain euglycemia during fasting. [muscle] Skeletal muscle tissue relies on products of fatty acid oxidation (FAO) during conditions of metabolic stress: fasting, prolonged exercise, febrile illness. Fasting-induced hypoglycemia and rhabdomyolysis are characteristic features of FAO disorders including very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (VLCADD). However, the pathophysiological mechanisms that underlie the connection between FAO dysfunction and skeletal muscle dysfunction are not known. Here, we investigated the transcriptional response in skeletal muscle tissue (gastrocnemius) to the FAO defect in a model of VLCADD: the long-chain acyl-CoA dehydrogenase (LCAD) knockout (KO) mouse. We found that differentially expressed genes in the muscle were associated with molecular networks annotated for the cellular response to starvation from population-based models. To validate the association between the starvation response and FAO, we pharmacologically inhibited both glucocorticoid signaling and FAO in a model of fasting and observed that mice depleted in both pathways lost less weight during fasting and became hypoglycemic. These findings implicate glucocorticoid signaling as a candidate modifier of the cellular response to starvation in muscle tissue in the context of FAO disorders including VLCADD.

2024-10-26 | GSE186648 | GEO

CRISPR/Cas9 screens reveal that hexokinase 2 enhances cancer stemness and tumorigenicity

Project description:We identified that HK2 facilitate the maintenance and self-renewal of liver cancer stem cells (CSCs). Moreover, HK2 exerts its function by enhancing the accumulation of acetyl-CoA and epigenetically activating the transcription of acyl-CoA synthetase long chain family member 4 (ACSL4), leading to an increase in fatty acid β-oxidation (FAO) activity.

2022-05-06 | GSE184798 | GEO

Liver mRNA expression in 25 mice with or without genetic defects of mitochondrial fatty acid oxidation (Acadl and Acadvl knockout) using RNA sequencing

Project description:full title: A mitochondrial long-chain fatty acid oxidation defect in a mouse model leads to dysregulation of plasma long-chain acylcarnitines, dysregulation of plasma amino acids, and an increased reliance on glucocorticoid signaling to maintain euglycemia during fasting. [liver] The liver is a major source of energy substrates during metabolic stress: fasting, prolonged exercise, febrile illness. Fasting-induced hypoglycemia is a characteristic feature of FAO disorders including very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (VLCADD). However, the pathophysiological mechanisms that underlie the diversity of clinical presentation of FAO dysfunction are not known. Here, we investigated the transcriptional response in liver tissue to the FAO defect in a model of VLCADD: the long-chain acyl-CoA dehydrogenase (LCAD) knockout (KO) mouse. We found that differentially expressed genes from the liver were associated with molecular networks annotated for fatty acid oxidation and cholesterol biosynthesis from population-based networks.

2024-10-26 | GSE186613 | GEO

Capase-1 cleaves PPARg for potentitating the pro-tumor action of TAMs

Project description:Tumor-associated macrophages (TAMs) are increasingly viewed as a target of great relevance in the tumor microenvironment, because of their important role in cancer progression and metastasis. However, the endogenous regulatory mechanisms underlying TAM differentiation remain largely unknown. Here, we report that caspase-1 promotes TAM differentiation by cleaving peroxisome proliferator-activated receptor gamma (PPARγ) at Asp64, thus generating a 41 kDa fragment. This truncated PPARγ translocates to mitochondria, where it directly interacts with medium-chain acyl-CoA dehydrogenase (MCAD). This binding event attenuates MCAD activity and inhibits fatty acid oxidation, thereby leading to the accumulation of lipid droplets and promoting TAM differentiation. Furthermore, the administration of caspase-1 inhibitors or the infusion of bone marrow-derived macrophages (BMDMs) genetically engineered to overexpress murine MCAD markedly suppresses tumor growth. Therefore, targeting the caspase-1/PPARγ/MCAD pathway might be a promising therapeutic approach to prevent tumor progression.

2017-06-14 | GSE99960 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data