ChIP-Seq to identify the enrichement of histone acetylation on the promoter of FASN and ACLY in tumors with BCAA dietary interventions.
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE240663 | GEO | 2023/10/10
REPOSITORIES: GEO
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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
Project description:We used RNA-Seq to ask whether the transcripts for the proposed BCKDH subunits are upregulated in wild-type plants subjected to prolonged darkness. These experiments were performed using rosette leaves from 5-week-old, short-day-grown (8h light/16h dark) Col-0 wild-type plants moved to constant darkness for 6h, 24h, 48h and 72h, and grown in short day for 72h as control. The transcripts of eight BCAA catabolism genes were increased nine- to 400-fold within the first 6h of prolonged darkness, and remained high until the last time point. These results are consistent with the hypothesis that BCAA catabolic enzymes - including BCKDH subunits E1A1, E1B1, E1B2 and E2 - have one or more physiological roles in the dark. Rosette leaf mRNA profiles of 5-week old Col wild type (WT, CS60000) and BCAA catabolic mutants ivd1-2 and hml1-2 were generated byRNA sequencing, in duplicate, using Illumina HiSeq2500.
2015-04-16 | E-GEOD-67956 | biostudies-arrayexpress
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.
2014-04-13 | GSE37243 | GEO
Project description:In order to propagate a solid tumor, cancer cells must adapt to and survive under various tumor microenvironment (TME) stresses, such as hypoxia or lactic acidosis. To systematically identify genes that modulate cancer cell survival under stresses, we performed genome-wide shRNA screens under hypoxia or lactic acidosis. We discovered that genetic depletion of acetyl-CoA carboxylase (ACACA or ACC1) or ATP citrate lyase (ACLY) protected cancer cells from hypoxia-induced apoptosis. Additionally, loss of ACLY or ACC1 reduced levels and activities of the oncogenic transcription factor ETV4. Silencing ETV4 also protected cells from hypoxia-induced apoptosis and led to remarkably similar transcriptional responses as with silenced ACLY or ACC1, including an anti-apoptotic program. Metabolomic analysis found that while α-ketoglutarate levels decrease under hypoxia in control cells, α-ketoglutarate is paradoxically increased by hypoxia when ACC1 or ACLY are depleted. Supplementation with α-ketoglutarate rescued the hypoxia-induced apoptosis and recapitulated the decreased expression and activity of ETV4 via an epigenetic mechanism. Therefore, ACC1 and ACLY regulate the levels of ETV4 under hypoxia via increased α-ketoglutarate. These results reveal that ACC1/ACLY- α-ketoglutarate-ETV4 is a novel means by which metabolic states regulate transcriptional output for life vs. death decisions under hypoxia. Since many lipogenic inhibitors are under investigation as cancer therapeutics, our findings suggest that the use of these inhibitors will need to be carefully considered with respect to oncogenic drivers, tumor hypoxia, progression and dormancy. More broadly, our screen provides a framework for studying additional tumor cell stress-adaption mechanisms in the future. DESIGN: H1975 lung cancer cells transduced with a scramble shRNA hairpin or two different shRNAs against ACLY, ACC1, or ETV4 under hypoxia.
2015-12-10 | E-GEOD-61286 | biostudies-arrayexpress
Project description:To investigate the regulatory role of ACLY activation in EC functions, we treated HUVEC with ACLY inhibitor BMS-303141 before LPS stimuli. We then performed gene expression profiling analysis using data obtained from RNA-seq of HUVEC lysates.
2023-09-11 | GSE216178 | GEO
Project description:We examined FASN knockdown LNCaP cells obtained by shRNA transduction with Mission lentiviral transduction particles (SHCLNV-NM 00410, TRCN3128, Sigma) (FASN-RNAi cells). In this study, we used cells transfected with non-targeting shRNA as a control (control-RNAi cells). The expression of genes related to cellular proliferation (phospholipase A2, group IVA, PLA2G4A; tensin 3, TNS3; glypican 4 GPC4), cell adhesion and extracellular matrix organization [peroxidasin homolog (Drosophila) PXDN; sarcoglycan epsilon, SGCE; von Willebrand factor, VWF; hydroxysteroid (17-beta) dehydrogenase 12, HSD17B12; cysteine-rich secretory protein LCCL domain containing 2, CRISPLD2], and cell motility (TNS3, RAP2B member of RAS oncogene family, RAP2B) were shown to be down-regulated by FASN inhibition with RNAi. FASN inhibition led to down-regulation of the PLA2G4A and HSD17B12 genes encoding phospholipase A2 and 17-beta hydroxysteroid dehydrogenase, respectively, which are the key enzymes related to production of an intracellular second messenger arachidonic acid and androgen hormones, both playing roles in promotion of tumor progression. We also found that the genes related to arachidonic acid signalling, including RGS2, SPAG16, VWF and RAP2B, were also suppressed with FASN inhibition. Gene expression profiling therefore demonstrated that FASN inhibition induces down-regulation of genes related to cell proliferation, cell adhesion, migration, and invasion, as well as the production of arachidonic acid and androgen hormones, both of which drive tumor progression. Total RNA isolation was performed with a Micro-to-Midi total RNA purification system (Invitrogen). The integrity of total RNAs was evaluated using an Agilent 2100 Bioanalyzer (Agilent Technologies). Low Input Quick Amp Labeling Kit, one-color (Agilent Technologies) was used to prepare Cy3-labelled target cRNA according to the manufacturer's instructions. Labeled cRNAs were hybridized with a SurePrint G3 Human GE 8M-CM-^W60K Microarrays (Agilent Technologies). Two separate hybridizations were performed for each sample. Array images were captured using a DNA Microarray Scanner (Agilent Technologies), and data were analyzed using Feature Extraction Software (Agilent Technologies) to obtain background-corrected signal intensities. The data were further analysed with GeneSpring GX Software (Version 11.0, Agilent Technologies). After filtering of data, mRNAs differentially expressed in target versus control were considered using the Fisher exact test, followed by multiple corrections using the Benjamini and Hochberg false discovery rate (FDR) method. Gene sets with a FDR q-value < 0.05 were considered significant.
2012-07-09 | E-GEOD-39183 | biostudies-arrayexpress
Project description:The fatty acid synthase (FASN) is the major fat synthesizing enzyme. FASN is an indispensable enzyme because mice with genetic deletion of Fasn are not viable. Apart from its physiological function, previous studies indicated that FASN could also exert a pathophysiological role, in the heart, because patients with heart failure showed up-reguation of FASN. To investigate the in vivo function of FASN up-regulation in the heart, we generated mice with myocardium-specific expression of FASN under control of the alpha-MHC promoter. Two different founder lines were generated with high and low FASN over-expression. Microarray gene expression profiling of heart tissue was performed of heart tissue from transgenic mice with high and low FASN expression Microarray gene expression profiling was performed with heart tissue isolated from three study groups: (i) Transgenic mice with high cardiac FASN expression, (ii) transgenic mice with low cardiac FASN expression, and (iii) B6 control mice.
2013-07-31 | E-GEOD-49351 | biostudies-arrayexpress
Project description:The branched-chain amino acid (BCAA) metabolism plays pleiotropic roles in homeostasis. Here we show that human acute leukemia-initiating cells (LICs), but not normal hematopoietic stem cells, are heavily addicted to the BCAA metabolism, irrespective of myeloid or lymphoid types. To clarify how BCAA metabolism affect the gene expression of human acute leukemia cells, we examined the gene expression alteration in human acute leukemia cell lines in control and BCAA-resrticted culture conditions.
2019-07-01 | GSE131815 | GEO
Project description:The branched-chain amino acid (BCAA) metabolism plays pleiotropic roles in homeostasis. Here we show that human acute leukemia-initiating cells (LICs), but not normal hematopoietic stem cells, are heavily addicted to the BCAA metabolism, irrespective of myeloid or lymphoid types. To clarify how BCAA metabolism affect the gene expression of human acute leukemia cells, we examined the gene expression alteration in human acute leukemia cell lines in control and BCAA-resrticted culture conditions.
2019-07-01 | GSE131814 | GEO
Project description:We examined FASN knockdown LNCaP cells obtained by shRNA transduction with Mission lentiviral transduction particles (SHCLNV-NM 00410, TRCN3128, Sigma) (FASN-RNAi cells). In this study, we used cells transfected with non-targeting shRNA as a control (control-RNAi cells). The expression of genes related to cellular proliferation (phospholipase A2, group IVA, PLA2G4A; tensin 3, TNS3; glypican 4 GPC4), cell adhesion and extracellular matrix organization [peroxidasin homolog (Drosophila) PXDN; sarcoglycan epsilon, SGCE; von Willebrand factor, VWF; hydroxysteroid (17-beta) dehydrogenase 12, HSD17B12; cysteine-rich secretory protein LCCL domain containing 2, CRISPLD2], and cell motility (TNS3, RAP2B member of RAS oncogene family, RAP2B) were shown to be down-regulated by FASN inhibition with RNAi. FASN inhibition led to down-regulation of the PLA2G4A and HSD17B12 genes encoding phospholipase A2 and 17-beta hydroxysteroid dehydrogenase, respectively, which are the key enzymes related to production of an intracellular second messenger arachidonic acid and androgen hormones, both playing roles in promotion of tumor progression. We also found that the genes related to arachidonic acid signalling, including RGS2, SPAG16, VWF and RAP2B, were also suppressed with FASN inhibition. Gene expression profiling therefore demonstrated that FASN inhibition induces down-regulation of genes related to cell proliferation, cell adhesion, migration, and invasion, as well as the production of arachidonic acid and androgen hormones, both of which drive tumor progression.
2012-07-10 | GSE39183 | GEO