Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Effect of SREBP2 silencing on gene expression of THP-1 monocytes under hypoxic condition

ABSTRACT: Monocyte infiltrate hypoxic tumor center to initiate pro-tumorigenic immune response and angiogenesis, however the detailed mechanism and responsible metabolic pathway was not investigated. Here we report that monocyte macrophage lineage cells are uniquely responsive to hypoxia compared to cancer cells and fibroblasts, upregulating cholesterol biosynthesis through SREBP2 regulation. Disruption of SREBP2 offsets upregulation of hypoxia-induced cholesterol biosynthesis gene expression. In addition, hypoxia-induced SREBP2 activation is lineage-dependent, and this activation is lost when monocyte matures to macrophage, suggesting a metabolic switch during differentiation. Finally, inhibiting cholesterol synthesis using statin reduces tumor burden and infiltration of pro-tumor immune cells into tumor center. In summary, SREBP2 regulated hypoxic response in monocytes are essential for tumor growth and is a potent drug target for novel therapeutic strategies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE239740 | GEO | 2023/08/14

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

ALOX15B controls macrophage cholesterol homeostasis via lipid peroxidation, ERK1/2 and SREBP2

Project description:Macrophage cholesterol homeostasis is crucial for health and disease and has been linked to the lipid-peroxidizing enzyme arachidonate 15-lipoxygenase type B (ALOX15B), albeit molecular mechanisms remain obscure. We performed global transcriptome and immunofluorescence analysis in ALOX15B-silenced primary human macrophages and observed a reduction of nuclear sterol regulatory element-binding protein (SREBP) 2, the master transcription factor of cellular cholesterol biosynthesis. Consequently, SREBP2-target gene expression was reduced as were the sterol biosynthetic intermediates desmosterol and lathosterol as well as 25- and 27-hydroxycholesterol. Mechanistically, suppression of ALOX15B reduced lipid peroxidation in primary human macrophages and thereby attenuated activation of mitogen-activated protein kinase ERK1/2, which lowered SREBP2 abundance and activity. Low nuclear SREBP2 rendered both, ALOX15B-silenced and ERK1/2-inhibited macrophages refractory to SREBP2 activation upon blocking the NPC intracellular cholesterol transporter 1. These studies suggest a regulatory mechanism controlling macrophage cholesterol homeostasis based on ALOX15B-mediated lipid peroxidation and concomitant ERK1/2 activation.

2024-04-07 | GSE208160 | GEO

Gene expression in PANC-1 and AsPC-1 human pancreatic carcinoma cells under hypoxia, nutrient starvation and low pH culture condition.

Project description:The conditions of the tumor microenvironment, such as hypoxia and nutrient starvation, play critical roles in cancer progression. However, the role of acidic extracellular pH in cancer progression is not studied as extensively as that of hypoxia. Here, we show that extracellular acidic pH (pH 6.8) triggered activation of sterol regulatory element-binding protein 2 (SREBP2) by stimulating nuclear translocation and promoter binding to its targets along with intracellular acidification. Interestingly, inhibition of SREBP2, but not SREBP1, suppressed the upregulation of low pH-induced cholesterol biosynthesis-related genes. Moreover, acyl-CoA synthetase short-chain family member 2 (ACSS2), a direct SREBP2 target, provided a growth advantage to cancer cells under acidic pH. Furthermore, acidic pH-responsive SREBP2 target genes were associated with reduced overall survival of cancer patients. Thus, our findings show that SREBP2 is a key transcriptional regulator of metabolic genes and progression of cancer cells, partly in response to extracellular acidification.

2017-01-25 | GSE93988 | GEO

Open chromatin region, histone acetylation, and SREBP2 binding in PANC-1 and AsPC-1 human pancreatic carcinoma cells under hypoxia, nutrient starvation and low pH culture condition.

2017-01-25 | GSE93982 | GEO

microarray analysis in SREBP2-knockdown cells under low pH (pH 6,8) culture conditions

2017-01-25 | GSE93980 | GEO

Cholesterol homeostatic regulator SREBP2 promotes macrophage alternative activation and allergic airway inflammation

Project description:Metabolic reprogramming is well-appreciated to be able to control macrophage activation. However, it remains unknown whether the SREBPs-lipogenesis pathway is involved in macrophage alternative (or M2) activation. Here, we showed that IL4-induced M2 activation was coupled with increased SREBP2 maturation and activated cholesterol biosynthetic pathway, while the SREBP1-fatty acid biosynthesis pathway remained unaffected after IL4 stimulation. Genetic or pharmacologic blockade of SREBP2 maturation significantly inhibited IL4-induced M2 activation independent of cholesterol. Instead, cholesterol inhibited M2 activation most likely through its feedback regulation of SREBP2 maturation. Mechanically, the upregulation of SREBP2 maturation was dependent on the activation of upstream MTOR, and mature SREBP2 increased the expression of KAZALD1 and subsequently activated the IGF1 signaling to promote IL4-induced M2 activation. Consistently, myeloid-specific Scap deficiency markedly decreased the number of M2 macrophages in the lung and attenuated the HDM-induced allergic airway inflammation. Taken together, these findings highlight a critical role for cholesterol homeostatic regulator SREBP2 in M2 activation, which advances our understanding of the regulation of immunometabolism for M2 activation and points to new opportunities for therapeutic control of M2 activation and allergic airway inflammation.

2023-04-30 | GSE188356 | GEO

Genome-wide maps of Qki-5, Srebp2, and Pol II in oligodendrocytes

Project description:We found the genome-wide co-localization of Qki-5 and Srebp2. Notably, the genomic distribution analysis revealed that Qki-5 and Srebp2 highly co-occupied the regions of the promoter/transcription start site (TSS), where active transcription was taken place in a oligodendrocyte-specific manner, which was indicated by Pol II binding events. GO analysis of the genes whose promoters were co-bound by Qki-5, Srebp2, and Pol II showed a significant enrichment of the Srebp2-mediated cholesterol biosynthesis pathway, and Qki depletion led to reduced recruitment of Srebp2 and Pol II on the promoters of the genes involved in cholesterol biosynthesis. These data suggest Qki-5 as a potential transcription co-activator of Srebp2-mediated cholesterol biosynthesis in oligodendrocytes.

2021-05-10 | GSE144756 | GEO

Genome-wide maps of QKI-5, SREBP2, and POL II in eye lens cells

Project description:We found the genome-wide co-binding of QKI-5 and SREBP2. Notably, the genomic distribution analysis revealed that the co-binding events between QKI-5 and SREBP2 highly occurred at the regions of the promoter/transcription start site (TSS), where active transcription was taken place in a lens cell-specific manner, which was indicated by POL II binding events. Cellular pathway analysis of the genes whose promoters were co-bound by QKI-5, SREBP2, and POL II showed a significant enrichment of the SREBP2-medaited cholesterol biosynthesis pathway, and QKI depletion led to reduced co-occupancies of SREBP2 and POL II on the promoters of the genes involved in cholesterol biosynthesis. These data suggest QKI-5 as a potential transcription co-activator mediating SREBP2-dependent cholesterol biosynthesis in eye lens cells.

2021-01-29 | GSE144757 | GEO

The mechanistic studies of GATA1 regulation of SREBP2 in G1-ER4 cells

Project description:In our work, we uncovered a critical role for cholesterol homeostasis in terminal erythropoiesis. The master transcriptional factor GATA1 binds to Sterol-regulatory element binding protein 2 (SREBP2) to downregulate cholesterol biosynthesis, leading to a gradual reduction in intracellular cholesterol levels. To reveal genetic interactions and epistatic relations between GATA1 and SREBP2 on depth at the whole genome level, we performed RNA sequencing to analyze the gene expression profiles change between treated with Vehicle or β-estradiol in overexpressing active SREBP2 G1E-ER4 cells.

2022-02-08 | GSE184002 | GEO

TNF promotes SREBP activity to regulate macrophage polarization and tissue repair [scRNA-seq]

Project description:TNF-mediated macrophage polarization is important for inflammatory disease pathogenesis, but mechanisms that regulate polarization are not well understood. Transcriptomic and epigenomic analysis of the TNF response in primary human macrophages revealed late phase activation of SREBP2, the master regulator of cholesterol biosynthesis genes. TNF stimulation extended the genomic profile of SREBP2 occupancy to include binding to and activation of inflammatory and interferon response genes independently of its functions in sterol metabolism. Genetic ablation of SREBP function shifted the balance of macrophage polarization from M1 to an M2-like reparative phenotype in peritonitis and skin wound healing models. Genetic ablation of SREBP activity in myeloid cells or topical pharmacological inhibition of SREBP improved skin wound healing under homeostatic and chronic inflammatory conditions. Our results identify a new function and mechanism of action for SREBP2 in augmenting TNF-induced M1 macrophage polarization and inflammation, and open therapeutic avenues for promoting wound repair.

2019-04-03 | GSE129225 | GEO

TNF promotes SREBP activity to regulate macrophage polarization and tissue repair [RNA-seq]

2019-04-03 | GSE129210 | GEO