Peroxisomal β-oxidation enzyme, DECR2, regulates lipid metabolism and promotes treatment resistance in advanced prostate cancer
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ABSTRACT:
PROVIDER: PRJNA903079 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR22330823_1.fastq.gz | Fastqsanger.gz | |||
| SRR22330823_2.fastq.gz | Fastqsanger.gz | |||
| SRR22330824_1.fastq.gz | Fastqsanger.gz | |||
| SRR22330824_2.fastq.gz | Fastqsanger.gz | |||
| SRR22330825_1.fastq.gz | Fastqsanger.gz |
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Project description:Peroxisomes are central metabolic organelles that have key roles in fatty acid homeostasis, including β-oxidation, and emerging evidence has linked aberrant peroxisome metabolism to cancer development and progression. While targeting mitochondrial β-oxidation in prostate cancer (PCa) has gained significant attention in recent years, the contribution of peroxisomal β-oxidation (perFAO) to PCa tumorigenesis is comparatively unexplored. Herein, we explored the therapeutic efficacy of targeting perFAO in PCa cells and clinical prostate tumours, and subsequently identified peroxisomal 2,4-dienoyl CoA reductase 2 (DECR2), as a key therapeutic target. DECR2 is markedly upregulated in clinical PCa, most notably in metastatic castrate-resistant PCa. Depletion of DECR2 significantly suppressed proliferation, migration, and 3D growth of a range of CRPC and enzalutamide-resistant PCa cell lines, and inhibited LNCaP tumour growth and proliferation in vivo. Using transcriptomic and lipidomic analyses, we determined that DECR2 influences cell cycle progression and lipid metabolism to enable tumour cell proliferation. We further demonstrated a novel role for perFAO in driving resistance to standard-of-care androgen receptor pathway inhibition, using genetic and pharmacological approaches to alter DECR2/perFAO in treatment-resistant PCa cells. Our findings highlight a need to focus on peroxisomes to suppress tumour cell proliferation and reveal new therapeutic targets for advanced, treatment-resistant PCa.
2023-12-31 | GSE218282 | GEO
Project description:Patients lacking multifunctional protein 2, the central enzyme of the peroxisomal β-oxidation pathway, develop retinopathy. This metabolic pathway is involved in the metabolism of very long chain (VLCFAs) and polyunsaturated (PUFAs) fatty acids, which are enriched in the photoreceptor outer segments (POS). The molecular mechanisms underlying the retinopathy remain however elusive. Here, we report that Mfp2-/- mice display decreased retinal function already at the age of 3 weeks, which is accompanied by a profound shortening of the photoreceptor outer and inner segments, but with preserved photoreceptor ultrastructure. Furthermore, Mfp2-/- retinas exhibit severe changes in gene expression with downregulation of genes involved in the phototransduction pathway and upregulation of inflammation related genes. Lipid profiling of the retina of Mpf2-/- mice revealed a profound reduction of DHA-containing phospholipids. This was likely due to a hampered systemic supply and retinal traffic of this PUFA, although we cannot exclude that the local defect of peroxisomal β-oxidation contributes to this DHA decrease. Moreover, VLC-PUFAs were also reduced, except those containing ≥34 carbons that accumulated. The latter suggests that there is an uncontrollable elongation of retinal PUFAs. In conclusion, we showed that intact peroxisomal β-oxidation is indispensable for retinal integrity, most likely by maintaining PUFA homeostasis.
2021-01-31 | GSE163770 | GEO
Project description:Epigenetic markers such as histone acetylation and DNA methylation determine chromatin organization. In eukaryotic cells, metabolites from organelles or the cytosol affect epigenetic modifications. However, the relationships between metabolites and epigenetic modifications are not well understood in plants. We found that peroxisomal acyl-CoA oxidase 4 (ACX4), an enzyme in the fatty acid β-oxidation pathway, is required for suppressing the silencing of some endogenous loci as well as Pro35S:NPTII in the ProRD29A:LUC/C24 transgenic line. The acx4 mutation reduces nuclear histone acetylation and increases DNA methylation at the NOS terminator of Pro35S:NPTII, and at some endogenous genomic loci, which are also targeted by the demethylation enzyme REPRESSOR OF SILENCING 1 (ROS1). Furthermore, mutations in multifunctional protein 2 (MFP2) and 3-ketoacyl-CoA thiolase-2 (KAT2/PED1/PKT3), two enzymes in the last two steps of the β-oxidation pathway, lead to similar patterns of DNA hypermethylation as in acx4. Thus, metabolites from fatty acid β-oxidation in peroxisomes are closely linked to nuclear epigenetic modifications, which may affect diverse cellular processes in plants.
2018-04-25 | GSE98214 | GEO
Project description:Distinct retrograde signaling pathways have been identified for several cellular organelles. These pathways are important to maintain the function of these organelles in response to organelle-specific stress. Using Caenorhabditis elegans, we show for the first time that such a retrograde signaling also exists for peroxisomes. Analysis of the C. elegans transcriptome revealed that peroxisomal import stress caused by the knock-down of the peroxisomal matrix protein import receptor prx-5/PEX5 induces the compensatory up-regulation of genes involved in defense response and lipid metabolic processes, especially peroxisomal beta oxidation. We, therefore, propose that the peroxisomal retrograde signaling participates in the maintenance of peroxisomal function in response to peroxisomal import stress.
2020-12-19 | GSE156318 | GEO
Project description:Robust tissue regeneration relies on extensive stem cell self-renewal. However, the molecular mechanisms promoting stem cell self-renewal during regeneration remain unclear. Here we investigate the role of peroxisomes, a key metabolic organelle, in regulating hematopoietic stem cells (HSCs). We found that disrupting peroxisome biogenesis by deleting Pex5 does not significantly impact HSC number or hematopoiesis at steady state. Strikingly, Pex5-deficient HSCs self-renew extensively and give rise to robust multilineage reconstitution upon multiple rounds of serial transplantation into recipients. Pex5-deficient HSCs are more resistant to stress and have enhanced capacity to regenerate the hematopoietic system following chemo drug treatment or irradiation. Deletion of Pex5 promotes the expansion of HSCs and hematopoietic progenitors with extensive serial ex vivo plating capacity. Pharmacological inhibition of peroxisomal β-oxidation also promotes extensive plating by HSCs and hematopoietic progenitors. We propose that intervening in peroxisomal β-oxidation can be exploited to promote HSC and progenitor function for regenerative medicine.
2025-09-01 | GSE294155 | GEO
Project description:BackgroundPeroxisomes are central metabolic organelles that have key roles in fatty acid homoeostasis. As prostate cancer (PCa) is particularly reliant on fatty acid metabolism, we explored the contribution of peroxisomal β-oxidation (perFAO) to PCa viability and therapy response.MethodsBioinformatic analysis was performed on clinical transcriptomic datasets to identify the perFAO enzyme, 2,4-dienoyl CoA reductase 2 (DECR2) as a target gene of interest. Impact of DECR2 and perFAO inhibition via thioridazine was examined in vitro, in vivo, and in clinical prostate tumours cultured ex vivo. Transcriptomic and lipidomic profiling was used to determine the functional consequences of DECR2 inhibition in PCa.ResultsDECR2 is upregulated in clinical PCa, most notably in metastatic castrate-resistant PCa (CRPC). Depletion of DECR2 significantly suppressed proliferation, migration, and 3D growth of a range of CRPC and therapy-resistant PCa cell lines, and inhibited LNCaP tumour growth and proliferation in vivo. DECR2 influences cell cycle progression and lipid metabolism to support tumour cell proliferation. Further, co-targeting of perFAO and standard-of-care androgen receptor inhibition enhanced suppression of PCa cell proliferation.ConclusionOur findings support a focus on perFAO, specifically DECR2, as a promising therapeutic target for CRPC and as a novel strategy to overcome lethal treatment resistance.
| S-EPMC10912652 | biostudies-literature
Project description:Elevated circulating lipid levels are known risk factors for cardiovascular diseases (CVD). In order to examine the effects of quercetin on hepatic lipid metabolism and detailed serum lipid profiles, mice received a mild-high-fat diet without (control) or with supplementation of 0.33% (w/w) quercetin for 12 weeks. Gas chromatography and 1H nuclear magnetic resonance were used to measure quantitatively serum lipid profiles and whole genome microarray analysis was used to identify the responsible mechanisms in liver. There were no significant differences found in mean body weight, energy intake and hepatic lipid accumulation between the quercetin and control group. In serum of quercetin-fed mice, TG levels were decreased with 15%, poly unsaturated fatty acids (PUFA) were increased with 14% and saturated fatty acids were decreased. Palmitic acid, oleic acid, and linoleic acid were all decreased in quercetin-fed mice by 9-15%. Both palmitic acid and oleic acid can be oxidized by omega-oxidation. Indeed, gene expression profiling showed that quercetin increased hepatic lipid metabolism, especially omega-oxidation. At the gene level, this was reflected by the up regulation of cytochrome P450 (Cyp) 4a10, Cyp4a14, Cyp4a31 and Acyl-CoA thioesterase 3 (Acot3). Two relevant regulators, Cytochrome P450 oxidoreductase (Por, rate limiting for cytochrome P450s) and the transcription factor Constitutive androstane receptor (Car; official symbol Nr1i3) were also up regulated in the quercetin-fed mice. We conclude that quercetin intake increased hepatic lipid omega-oxidation and lowered corresponding circulating lipid levels, a process that may involve Por and Car, and results in a potential beneficial CVD preventive effect. Liver samples were obtained from 36 C57BL/6J male adult mice. All mice started with a three week adaptation phase, in which they were fed a mild-high-fat diet. 12 mice were sacrificed immediately after the adaptation phase (t=0). The other 24 mice received the mild-high-fat diet without (HF) or with supplementation of 0.33% (w/w) quercetin (HF-Q) for 12 weeks.
2013-02-05 | E-GEOD-39140 | biostudies-arrayexpress
Project description:The aim is to study the function of peroxisomal NAD-malate dehydrogenase in fatty acid beta-oxidation, glyoxylate cycle and photorespiration. Both peroxisomal MDH genes (At2g22780 and At5g09660) have been knocked out with T-DNA insertions and a double mutant made. Double mutant seedlings are blocked in beta-oxidation - they are 2,4DB resistant and beta-oxidation genes are repressed. They carry out glyoxylate cycle as normal. Plants grow well in soil and produce seed. Microarray analysis will tell us the extent of changes in gene expression in the mutant. For microarray analysis seeds are stratified at 4 C on agar medium with 1/2 strength M&S salts and 1% sucrose for 2 days, then seedlings grown for 2 days at 20 C in the light (100 umol/m2/s). Triplicate samples will be grown for mutant and wild type (col-0) and RNA isolated from each. Experimenter name = Itsara Pracharoenwattana; Experimenter phone = 0131 650 5316; Experimenter fax = 0131 650 5392; Experimenter department = Institute of Molecular Plant Sciences; Experimenter institute = University of Edinburgh; Experimenter address = Daniel Rutherford Building University of Edinburgh; Experimenter address = The King's Buildings; Experimenter address = Edinburgh; Experimenter zip/postal_code = EH9 3JH; Experimenter country = UK Experiment Overall Design: 6 samples were used in this experiment
2008-06-13 | E-GEOD-5641 | biostudies-arrayexpress
Project description:The aim is to study the function of peroxisomal NAD-malate dehydrogenase in fatty acid beta-oxidation, glyoxylate cycle and photorespiration. Both peroxisomal MDH genes (At2g22780 and At5g09660) have been knocked out with T-DNA insertions and a double mutant made. Double mutant seedlings are blocked in beta-oxidation - they are 2,4DB resistant and beta-oxidation genes are repressed. They carry out glyoxylate cycle as normal. Plants grow well in soil and produce seed. Microarray analysis will tell us the extent of changes in gene expression in the mutant. For microarray analysis seeds are stratified at 4 C on agar medium with 1/2 strength M&S salts and 1% sucrose for 2 days, then seedlings grown for 2 days at 20 C in the light (100 umol/m2/s). Triplicate samples will be grown for mutant and wild type (col-0) and RNA isolated from each. Experimenter name = Itsara Pracharoenwattana Experimenter phone = 0131 650 5316 Experimenter fax = 0131 650 5392 Experimenter department = Institute of Molecular Plant Sciences Experimenter institute = University of Edinburgh Experimenter address = Daniel Rutherford Building University of Edinburgh Experimenter address = The King's Buildings Experimenter address = Edinburgh Experimenter zip/postal_code = EH9 3JH Experimenter country = UK Keywords: genetic_modification_design
2007-01-08 | GSE5641 | GEO
Project description:Elevated circulating lipid levels are known risk factors for cardiovascular diseases (CVD). In order to examine the effects of quercetin on hepatic lipid metabolism and detailed serum lipid profiles, mice received a mild-high-fat diet without (control) or with supplementation of 0.33% (w/w) quercetin for 12 weeks. Gas chromatography and 1H nuclear magnetic resonance were used to measure quantitatively serum lipid profiles and whole genome microarray analysis was used to identify the responsible mechanisms in liver. There were no significant differences found in mean body weight, energy intake and hepatic lipid accumulation between the quercetin and control group. In serum of quercetin-fed mice, TG levels were decreased with 15%, poly unsaturated fatty acids (PUFA) were increased with 14% and saturated fatty acids were decreased. Palmitic acid, oleic acid, and linoleic acid were all decreased in quercetin-fed mice by 9-15%. Both palmitic acid and oleic acid can be oxidized by omega-oxidation. Indeed, gene expression profiling showed that quercetin increased hepatic lipid metabolism, especially omega-oxidation. At the gene level, this was reflected by the up regulation of cytochrome P450 (Cyp) 4a10, Cyp4a14, Cyp4a31 and Acyl-CoA thioesterase 3 (Acot3). Two relevant regulators, Cytochrome P450 oxidoreductase (Por, rate limiting for cytochrome P450s) and the transcription factor Constitutive androstane receptor (Car; official symbol Nr1i3) were also up regulated in the quercetin-fed mice. We conclude that quercetin intake increased hepatic lipid omega-oxidation and lowered corresponding circulating lipid levels, a process that may involve Por and Car, and results in a potential beneficial CVD preventive effect.
2013-02-05 | GSE39140 | GEO