Altered propionate metabolism contributes to tumor progression and aggressiveness
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ABSTRACT:
PROVIDER: PRJNA675592 | ENA |
REPOSITORIES: ENA
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Project description:The alteration of metabolic pathways is a critical strategy for cancer cells to attain the traits necessary for metastasis in disease progression. We found that dysregulation of propionate metabolism occurs through TGFbeta- and ERK2-driven downregulation of methylmalonyl-CoA epimerase (MCEE). MCEE downregulation occurs through a transcription factor Sp1/EGR1 switch at its promoter region, resulting in reduced flux through this anapleurotic pathway and leading to accumulation of methylmalonic acid (MMA), a byproduct of the propionate metabolism. MMA accumulation through alteration of propionate metabolism produces a pro-aggressive signature in breast and lung cancer cells and increases their metastatic potential. Altogether, we present a previously uncharacterized dysregulation of propionate metabolism as a novel contributor to cancer and a valuable potential target in the therapeutic treatment of metastatic carcinomas.
2022-01-28 | GSE161108 | GEO
Project description:Background. Short-chain fatty acids (SCFAs), mainly acetate, propionate and butyrate, are produced by gut microbiota through fermentation of complex carbohydrates that cannot be digested by the human host. They affect gut health and can contribute at the distal level to the pathophysiology of several diseases, including renal pathologies. Methods. SCFA levels were measured in chronic kidney disease (CKD) patients (n = 54) at different stages of the disease and associations with renal function and inflammation parameters were examined. The impact of propionate and butyrate in pathways triggered in tubular cells under inflammatory conditions was analysed using genome-wide expression assays. Finally, a pre-clinical mouse model of folic acid-induced transition from acute kidney injury to CKD was used to analyse the preventive and therapeutic potential of these microbial metabolites in the development of CKD. Results. Faecal levels of propionate and butyrate in CKD patients gradually reduce as the disease progresses, and do so in close association with established clinical parameters for serum creatinine, blood urea nitrogen and the estimated glomerular filtration rate. Propionate and butyrate jointly downregulated the expression of 103 genes related to inflammatory processes and immune system activation triggered by TNF-α in tubular cells. In vivo, the administration of propionate and butyrate, either before or soon after injury, respectively prevented and slowed the progression of damage. This was indicated by a decrease in renal injury markers, the expression of pro-inflammatory and pro-fibrotic markers, and recovery of renal function over the long term. Conclusions. Propionate and butyrate levels are associated with a progressive loss of renal function in CKD patients. Early administration of these SCFAs prevents disease advancement in a pre-clinical model of acute renal damage, thereby demonstrating their therapeutic potential independently of the gut microbiota.
2024-05-02 | GSE221506 | GEO
Project description:Propiogenic substrate catabolism and gut bacteria produce propionate, a post-translational protein modifier. Here, using a mouse model of propionic acidaemia (PA), we characterise how disturbances to propionate metabolism modify histones and affect cardiac gene expression and function. Plasma propionate was raised in PA mice, but male hearts accumulated a smaller propionyl-CoA excess, correlating with -alanine build-up. Raising -alanine experimentally in myocytes cultured under propionate-stress reduced propionyl-CoA and partially reversed the propionate-evoked metabolic disturbance. Female PA hearts manifested a moderate diastolic dysfunction phenotype, with raised diastolic [Ca2+], expanded end-systolic ventricular volume, and reduced stroke volume. Differentially-expressed genes included Pde9a and Mme that relate to contractile dysfunction through down-scaled cGMP signalling, consistent with phosphoproteome changes. Propionate was traced to histone H3 propionylation and increased acetylation genome-wide, including at Pde9a and Mme promoters, with more pronounced effects in female PA hearts. We link perturbed propionate metabolism to epigenetic changes that impact cardiac function.
2023-09-28 | GSE205837 | GEO
Project description:Propiogenic substrate catabolism and gut bacteria produce propionate, a post-translational protein modifier. Here, using a mouse model of propionic acidaemia (PA), we characterise how disturbances to propionate metabolism modify histones and affect cardiac gene expression and function. Plasma propionate was raised in PA mice, but male hearts accumulated a smaller propionyl-CoA excess, correlating with -alanine build-up. Raising -alanine experimentally in myocytes cultured under propionate-stress reduced propionyl-CoA and partially reversed the propionate-evoked metabolic disturbance. Female PA hearts manifested a moderate diastolic dysfunction phenotype, with raised diastolic [Ca2+], expanded end-systolic ventricular volume, and reduced stroke volume. Differentially-expressed genes included Pde9a and Mme that relate to contractile dysfunction through down-scaled cGMP signalling, consistent with phosphoproteome changes. Propionate was traced to histone H3 propionylation and increased acetylation genome-wide, including at Pde9a and Mme promoters, with more pronounced effects in female PA hearts. We link perturbed propionate metabolism to epigenetic changes that impact cardiac function.
2023-09-28 | GSE205836 | GEO
Project description:Propiogenic substrate catabolism and gut bacteria produce propionate, a post-translational protein modifier. Here, using a mouse model of propionic acidaemia (PA), we characterise how disturbances to propionate metabolism modify histones and affect cardiac gene expression and function. Plasma propionate was raised in PA mice, but male hearts accumulated a smaller propionyl-CoA excess, correlating with -alanine build-up. Raising -alanine experimentally in myocytes cultured under propionate-stress reduced propionyl-CoA and partially reversed the propionate-evoked metabolic disturbance. Female PA hearts manifested a moderate diastolic dysfunction phenotype, with raised diastolic [Ca2+], expanded end-systolic ventricular volume, and reduced stroke volume. Differentially-expressed genes included Pde9a and Mme that relate to contractile dysfunction through down-scaled cGMP signalling, consistent with phosphoproteome changes. Propionate was traced to histone H3 propionylation and increased acetylation genome-wide, including at Pde9a and Mme promoters, with more pronounced effects in female PA hearts. We link perturbed propionate metabolism to epigenetic changes that impact cardiac function.
2023-09-28 | GSE205835 | GEO
Project description:Propiogenic substrate catabolism and gut bacteria produce propionate, a post-translational protein modifier. Here, using a mouse model of propionic acidaemia (PA), we characterise how disturbances to propionate metabolism modify histones and affect cardiac gene expression and function. Plasma propionate was raised in PA mice, but male hearts accumulated a smaller propionyl-CoA excess, correlating with -alanine build-up. Raising -alanine experimentally in myocytes cultured under propionate-stress reduced propionyl-CoA and partially reversed the propionate-evoked metabolic disturbance. Female PA hearts manifested a moderate diastolic dysfunction phenotype, with raised diastolic [Ca2+], expanded end-systolic ventricular volume, and reduced stroke volume. Differentially-expressed genes included Pde9a and Mme that relate to contractile dysfunction through down-scaled cGMP signalling, consistent with phosphoproteome changes. Propionate was traced to histone H3 propionylation and increased acetylation genome-wide, including at Pde9a and Mme promoters, with more pronounced effects in female PA hearts. We link perturbed propionate metabolism to epigenetic changes that impact cardiac function.
2023-09-28 | GSE205834 | GEO
Project description:Fusobacterium nucleatum Reducing METTL3-mediated m6A Modification Contributes to Colorectal Cancer Aggressiveness
| PRJNA631745 | ENA
Project description: Not available
| S-EPMC8786899 | biostudies-literature
Project description:Propionate is a common three-carbon intermediate produced from the breakdown of propiogenic substrates, such as branched-chain amino acids and odd-numbered fatty acids, and by gut bacteria. Propionate can chemically modify proteins, and if this involves histones, it may underpin a disease-relevant link between short-chain acyls and gene expression in the heart. Here, we sought to characterize how propionate-dependent modifications to histones affect cardiac gene expression and contractile function in a mouse model producing elevated levels of propionate/propionyl-CoA. An adult mouse model of propionic acidaemia (PA) was used to investigate how propionate affects histones and gene expression in the heart, an organ strongly affected in PA patients. Mass spectrometry confirmed elevated plasma propionate in 8-week PA mice, reaching levels detected in PA patient serum. Metabolomic analyses confirmed a metabolic signature of PA, but male mice had enhanced propionate processing towards -alanine. Female PA hearts had expanded end-diastolic and end-systolic volumes, and weaker systolic contractions, without major electrocardiographic changes. Ca2+ signals were deranged in female PA mice (raised diastolic Ca2+), consistent with contractile dysfunction. Differentially-expressed genes (DEGs) included Pde9a and Mme, previously linked to cardiac dysfunction. These DEGs also responded to 48-h culture of wild-type myocytes with propionate as well as butyrate, an HDAC inhibitor, suggesting a role for increased histone acetylation alongside propionylation in inducing these genes. Indeed, histone acetylation (H3K27ac) and propionylation were elevated genome-wide in the PA heart and at the promoters of Pde9a and Mme. These propionate-associated epigenetic responses were more pronounced in female PA mice. The greater prominence of epigenetic, transcriptional, and functional responses in female PA mice, despite a mostly sex-indiscriminate overall metabolic milieu, argues that histone acylation plays a defining role in the cardiac phenotype. We conclude that perturbed propionate metabolism in vivo alters histone acylation and gene expression, which impacts cardiac contractile function.
2023-09-29 | PXD043513 | Pride
Project description:To investigate the effect of sodium propionate (SP) in enhancing the epithelial gene program via epigenetic remodelling in NSCLC, A549 cell line was treated with SP for 3 hours. Chromatin immunoprecipitation DNA-sequencing (ChIP-seq) was performed for the histone mark H3K27ac in A549 cell line treated with SP for 3 hours.
2023-02-15 | GSE224739 | GEO