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NAT10 depletion suppresses fatty acid metabolism in MCF7 breast cancer cells

ABSTRACT: NAT10 is an RNA cytidine transferase known to add acetyl group on RNA transcripts thereby promoting translational efficiency. It was reported that NAT10 regulates epithelial to mesenchymal transition (EMT), DNA damage, and cell proliferation in cancers. However, weather NAT10 regulates other crucial pathways is unknown. In our study we conducted gene expression profiling analysis using data obtained from RNA-seq of MCF7 NAT10 KO and scramble control. High throughput sequencing revealed fatty acid metabolism as the top enriched pathway with fatty acid metabolic genes such ELOVL6, ACSL1, ACSL3, ACSL4, ACADSB, and ACAT1 were found to be differentially down-regulated. Overall our results revealed NAT10 depletion suppresses fatty acid metabolism in MCF7.

ORGANISM(S): Homo sapiens

PROVIDER: GSE210086 | GEO | 2022/08/03

REPOSITORIES: GEO

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NAT10 modulates fatty acid metabolism of palmitate driven MCF7 in ac4C dependent manner

Project description:We show that non-toxic exogenous palmitate uptake in MCF7 cells promotes NAT10 expression and NAT10-dependent ac4C RNA modification. It was previously reported that NAT10 modulates the addition of ac4C on RNA transcripts in normal and cancer conditions. However, no study report the impact of NAT10 in palmitate driven cells. Here we performed RNA immunoprecipitation sequencing (RIP-seq) in palmitate loaded MCF7 knockdown with NAT10 siRNA. Based on the pathways and enrichment landscape identified. We found that ac4C peaks of fatty acid metabolic genes including ELOVL6, ACSL1, ACSL3, ACSL4, ACADSB and ACAT1 were significantly decreased upon knockdown with NAT10 siRNA. Overall, our results revealed the impact of NAT10 as a regulator of fatty acid metabolism in ac4C-dependent manner

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2014-09-29 | E-GEOD-51913 | biostudies-arrayexpress

Cardiac energy dependence on glucose activates metabolic genes controlled by mTOR

2014-09-29 | GSE51913 | GEO

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Project description:TNF-alpha has a number of pro-atherogenic effects in macrovascular endothelial cells, including induction of leukocyte adhesion molecules and chemokines. We investigated the role of acyl-CoA synthetase 3 (ACSL3) in the response of cultured human macrovascular endothelial cells to TNF-alpha. TNF-alpha induced ACSL3 both in human umbilical vein endothelial cells (HUVECs) and in human coronary artery endothelial cells (HCAECs). RNA sequencing demonstrated that knockdown of ACSL3 had no marked effects on the TNF-alpha transcriptome in HCAECs. Instead, ACSL3 was required for TNF-alpha-induced lipid droplet formation from fatty acids.

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Quantitative phosphoproteomic analysis reveals the regulatory networks of elovl6 on lipid and glucose metabolism in zebrafish

Project description:Elongation of very long-chain fatty acids protein 6 (Elovl6) has been reported to be associated with clinical treatments of a variety of metabolic diseases. However, there is no systematic and comprehensive study to reveal the regulatory role of Elovl6 in the mRNA, protein and phosphorylation levels. We established the first knock-out (KO), elovl6-/-, in zebrafish. Compared with wild type (WT) zebrafish, KO presented significant higher content of whole-body lipid and lower content of fasting blood glucose. We utilized RNA-Seq, tandem mass tag (TMT) labeling-based quantitative technology, and LC-MS/MS to perform the transcriptomic, proteomic, and phosphoproteomic analyses of livers from WT and elovl6-/- zebrafish. There were 734 differentially expressed genes (DEG) and 559 differentially expressed proteins (DEP) identified out of quantifiable 47251 transcripts and 5525 proteins between elovl6-/- and WT zebrafish. Meanwhile, 680 differentially expressed phosphoproteins (DEPP) with 1054 sites were found out of quantifiable 1230 proteins with 3604 sites. GO and KEGG analysis of the transcriptomic and proteomic data further suggested that the abnormal lipid metabolism and glucose metabolism in KO were mainly related to fatty acid degradation and biosynthesis, glycolysis/gluconeogenesis and PPAR signaling pathway. In the phosphoproteomics, some phosphoproteins and kinases critical for lipid metabolism and glucose metabolism, including ribosomal protein S6 kinase (Rps6kb), mitogen-activated protein kinase14 (Mapk14), and V-akt murine thymoma viral oncogene homolog 2, -like (Akt2l), were identified. These results allowed us to catch on the regulatory networks of elovl6 on lipid and glucose metabolism in zebrafish. To our knowledge, this is the first multi-omic study of zebrafish lacking elovl6, which provides strong datasets to better understand many lipid/glucose metabolic risks posed to human health.

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Metabolic and Transcriptional Alterations in the Early Stages of Cardiac Fuel Switch Hint at Novel mTOR-mediated Regulation of Hypertrophy [RNA-seq]

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Metabolic and Transcriptional Alterations in the Early Stages of Cardiac Fuel Switch Hint at Novel mTOR-mediated Regulation of Hypertrophy [Agilent Expression]

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Expression data by ACLY knockdown

Project description:De novo lipogenesis is activated in most cancers. Several lipogenic enzymes are implicated in oncogenesis and represent potential cancer therapeutic targets. RNA interference-mediated depletion of ATP citrate lyase (ACLY), the enzyme that catalyzes the first step of de novo lipogenesis, leads to growth suppression in a subset of human cancer cells. Here we demonstrate the molecular basis and potential biomarkers for ACLY-targeting therapy. First, suppression of cancer cell growth by ACLY depletion involves down-regulation of fatty acid elongase ELOVL6 at the transcriptional level. Lipid profiling revealed that ACLY depletion alters fatty acid composition in triglyceride; increased palmitate and decreased longer fatty acids, in accordance with ELOVL6 down-regulation. Second, ACLY depletion increases reactive oxygen species (ROS), whereas addition of antioxidant reduces ROS and attenuates the growth suppression. Third, ACLY depletion or ROS stimulation induce phosphorylation of AMP-activated protein kinase (AMPK), a sensor of energy and lipid metabolism. Analysis of various cancer cell lines revealed that the levels of AMPK phosphorylation (p-AMPK) correlate with the basal ROS levels, and that cancer cells with low basal p-AMPK (i.e., low basal ROS) levels are highly susceptible to ACLY depletion-mediated growth suppression. Finally, in clinical colon cancer tissues, p-AMPK levels are significantly decreased in aggressive tumors and correlate with the levels of 8-hydroxydeoxyguanosine, a hallmark of ROS stimulation. Together, these data suggest that ACLY inhibition suppresses cancer growth via palmitate-mediated lipotoxicity, and p-AMPK could be a predictive biomarker for its therapeutic outcome. Two cell lines are treated with ACLY siRNA. The samples include controls of each cell line.

2014-04-13 | E-GEOD-37243 | biostudies-arrayexpress

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