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Multi-omics characterization of the unsaturated fatty acid biosynthesis pathway in colon cancer.

ABSTRACT: The biosynthesis of unsaturated fatty acids is involved in the initiation and progression of colon adenocarcinoma (COAD). In this study, we aimed to investigate the multi-omics characteristics of unsaturated fatty acid biosynthesis-related genes and explore their prognostic value in colon cancer by analyzing the data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. An unsaturated fatty acid biosynthesis pathway related-genes enrichment score (BUFAS) was constructed utilizing the single sample gene set enrichment analysis (ssGSEA). We discovered that a high BUFAS was associated with longer overall survival (OS) in both the training and the validation sets. Multivariable analysis including the clinical characteristics further verified the independent prognostic value of the BUFAS in both the TCGA-COAD and the GSE39582 datasets. In addition, GSEA analysis revealed that BUFAS was positively associated with several signaling pathways, including MTORC1, peroxisome, and pathways related to fatty acid metabolism, while was negatively associated with other signaling pathways, such as hedgehog, NOTCH, and Wnt/beta-catenin pathway. Furthermore, in the COAD cell lines of the Genomics of Drug Sensitivity in Cancer (GDSC) database, we found that BUFAS was positively correlated with the drug sensitivities of cisplatin, gemcitabine, camptothecin, lapatinib, and afatinib, while was negatively correlated with that of ponatinib. Moreover, in the COAD single-cell transcriptomic dataset (GSE146771), the BUFAS varied among different cell types and was enriched in mast cells and fibroblasts. Taken together, the BUFAS we constructed could be used as an independent prognostic signature in predicting the OS and drug resistance of colon cancer. Unsaturated fatty acid biosynthesis pathway might serve as potential therapeutic targets for cancer treatment.

SUBMITTER: Chen L

PROVIDER: S-EPMC9442000 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Multi-omics characterization of the unsaturated fatty acid biosynthesis pathway in colon cancer.

Chen Ling L Yang Chang-Shun CS Chen Si-Dong SD Zhou Qiao-Xia QX Wang Guo-Qiang GQ Cai Shang-Li SL Li Wei-Hua WH Luo Hong-Zhi HZ

American journal of cancer research 20220815 8

The biosynthesis of unsaturated fatty acids is involved in the initiation and progression of colon adenocarcinoma (COAD). In this study, we aimed to investigate the multi-omics characteristics of unsaturated fatty acid biosynthesis-related genes and explore their prognostic value in colon cancer by analyzing the data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. An unsaturated fatty acid biosynthesis pathway related-genes enrichment score (BUFAS) was constructe ...[more]

PMID: 36119831

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Project description:BackgroundGlycerolipid metabolism is involved in the genesis and progression of colon cancer. The current study aims at exploring the prognostic value and potential molecular mechanism of glycerolipid metabolism-related genes in colon cancer from the perspective of multi-omics.MethodsClinical information and mRNA expression data of patients with colon cancer were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Single-sample gene set enrichment analysis (ssGSEA) was applied to calculate the glycerolipid metabolism-related gene enrichment score (GLMS). Univariable and multivariable Cox regression analyses were used to study the prognostic value of GLMS in TCGA-COAD and GSE39582 cohorts. The molecular mechanism of the prognostic factor was investigated via immune cell infiltration estimation and correlation analysis of cancer hallmark pathways. Single-cell transcriptomic dataset GSE146771 was used to identify the cell populations which glycerolipid metabolism targeted on.ResultsThe GLMS was found to be associated with tumor location and consensus molecular types (CMSs) of colon cancer in TCGA-COAD cohort (P < 0.05). Patients in the low-GLMS group exhibited poorer overall survival (OS) in TCGA cohort (P = 0.03; HR, 0.63; 95% CI, 0.42-0.94), which was further validated in the GSE39582 dataset (P < 0.001; HR, 0.57; 95% CI, 0.43-0.76). The association between the GLMS and OS remained significant in the multivariable analysis (TCGA cohort: P = 0.04; HR, 0.64; 95% CI, 0.42-0.98; GSE39582 cohort: P < 0.001; HR, 0.60; 95% CI, 0.45-0.80). The GLMS was positively correlated with cancer hallmark pathways including bile acid metabolism, xenobiotic metabolism, and peroxisome and negatively correlated with pathways such as interferon gamma response, allograft rejection, apoptosis, and inflammatory response (P < 0.05). Increased immune infiltration and upregulated expression of immune checkpoints were observed in patients with lower GLMS (P < 0.05). Single-cell datasets verified the different distribution of GLMS in cell subsets, with significant enrichment of GLMS in malignant cells and Tprolif cells.ConclusionWe demonstrated that GLMS was a potential independent prognostic factor for colon cancer. The GLMS was also correlated with several cancer hallmark pathways, as well as immune microenvironment.

Project description:BackgroundThe biosynthesis of unsaturated fatty acids (UFAs) has been implicated in the onset and advancement of breast cancer (BC). This study aimed to develop molecular subtypes and prognostic signatures for BC based on UFA-related genes (UFAGs).MethodsThis study integrates multi-omics and survival data from public databases to elucidate molecular classifications and risk profiles based on UFAGs. Consensus clustering and Lasso Cox regression methodologies are employed for subtype identification and risk signature development, respectively. Immune microenvironment assessment is conducted using CIBERSORT and ESTIMATE algorithms, while drug sensitivity and response to immunotherapy are evaluated via pRRophetic and TIDE methods. Gene set enrichment analysis augments signature characterization, followed by nomogram construction and validation.ResultsWe successfully identified two distinct BC molecular subtypes with significantly different prognoses utilizing UFAGs correlated with outcomes. A prognostic signature comprising three UFAGs [acetyl-CoA acyltransferase 1 (ACAA1), acyl-CoA thioesterase 2 (ACOT2), and ELOVL fatty acid elongase 2 (ELOVL2)] is developed, stratifying patients into high- and low-risk groups exhibiting divergent outcomes, clinicopathological traits, gene expression patterns, immune infiltration profiles, therapeutic susceptibility, and immunotherapy responses. The signature demonstrates robust prognostic performance in both training and validation cohorts, emerging as an independent predictor alongside age, which is integrated into a nomogram. Decision curve analysis highlights the nomogram's superiority over other factors in prognosis prediction. Calibration plots and receiver operating characteristic curves affirm its excellent performance in BC prognosis assessment.ConclusionsExpression profiles of UFAGs are associated with BC prognosis, enabling the creation of a risk signature with implications for understanding the molecular mechanisms underlying BC progression.

Project description:Two transcriptional regulators, the FadR activator and the FabR repressor, control biosynthesis of unsaturated fatty acids in Escherichia coli. FabR represses expression of the two genes, fabA and fabB, required for unsaturated fatty acid synthesis and has been reported to require the presence of an unsaturated thioester (of either acyl carrier protein or CoA) in order to bind the fabA and fabB promoters in vitro. We report in vivo experiments in which unsaturated fatty acid synthesis was blocked in the absence of exogenous unsaturated fatty acids in a ?fadR strain and found that the rates of transcription of fabA and fabB were unaffected by the lack of unsaturated thioesters. To examine the discrepancy between our in vivo results and the prior in vitro results we obtained active, natively folded forms of the E. coli and Vibrio cholerae FabRs by use of an in vitro transcription-translation system. We report that FabR bound the intact promoter regions of both fabA and fabB in the absence of unsaturated acyl thioesters, but bound the two promoters differently. Native FabR bound the fabA promoter region provided that the canonical FabR binding site is extended by inclusion of flanking sequences that overlap the neighbouring FadR binding site. In contrast, although binding to the fabB operator also required a flanking sequence, a non-specific sequence could suffice. However, unsaturated thioesters did allow FabR binding to the minimal FabR operator sites of both promoters which otherwise were not bound. Thus unsaturated thioester ligands were not essential for FabR/target DNA interaction, but acted to enhance binding. The gel mobility shift data plus in vivo expression data indicate that despite the remarkably similar arrangements of promoter elements, FadR predominately regulates fabA expression whereas FabR is the dominant regulator of fabB expression. We also report that E. coli fabR expression is not autoregulated. Complementation, qRT-PCR and fatty acid composition analyses demonstrated that V. cholerae FabR was a functional repressor of unsaturated fatty acid synthesis. However, in contrast to E. coli, gel mobility shift assays indicated that neither E. coli nor V. cholerae FabRs bound the V. cholerae fabB promoter, although both proteins efficiently bound the V. cholerae fabA promoter. This asymmetry was shown to be due to the lack of a FabR binding site within the V. cholerae fabB promoter region.

Project description:Objectives: Serine metabolism is essential for tumor cells. Endogenous serine arises from de novo synthesis pathways. As the rate-limiting enzyme of this pathway, PHGDH is highly expressed in a variety of tumors including colon cancer. Therefore, targeted inhibition of PHGDH is an important strategy for anti-tumor therapy research. However, the specific gene expression and metabolic pathways regulated by PHGDH in colon cancer are still unclear. Our study was aimed to clarified the role of PHGDH in serine metabolism in colon cancer to provide new knowledge for in-depth understanding of serine metabolism and PHGDH function in colon cancer. Methods: In this study, we analyzed the gene expression and metabolic remodeling process of colon cancer cells (SW620) after targeted inhibition of PHGDH by gene transcriptomics and metabolomics. LC-MS analysis was performed in 293T cells to PHGDH gene transcription and protein post-translational modification under depriving exogenous serine. Results: We found that amino acid transporters, amino acid metabolism, lipid synthesis related pathways compensation and other processes are involved in the response process after PHGDH inhibition. And ATF4 mediated the transcriptional expression of PHGDH under exogenous serine deficiency conditions. While LC-MS analysis of post-translational modification revealed that PHGDH produced changes in acetylation sites after serine deprivation that the K289 site was lost, and a new acetylation site K21was produced. Conclusion: Our study performed transcriptomic and metabolomic analysis by inhibiting PHGDH, thus clarifying the role of PHGDH in gene transcription and metabolism in colon cancer cells. The mechanism of high PHGDH expression in colon cancer cells and the acetylation modification that occurs in PHGDH protein were also clarified by serine deprivation. In our study, the role of PHGDH in serine metabolism in colon cancer was clarified by multi-omics analysis to provide new knowledge for in-depth understanding of serine metabolism and PHGDH function in colon cancer.

Dataset Information

Multi-omics characterization of the unsaturated fatty acid biosynthesis pathway in colon cancer.

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Multi-omics characterization of the unsaturated fatty acid biosynthesis pathway in colon cancer.

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