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Transcriptional hallmarks of cancer cell lines reveal an emerging role of branched chain amino acid catabolism.

ABSTRACT: A comparative analysis between cancer cell lines and healthy dividing cells was performed using data (289 microarrays and 50 RNA-seq samples) from 100 different cancer cell lines and 6 types of healthy stem cells. The analysis revealed two large-scale transcriptional events that characterize cancer cell lines. The first event was a large-scale up-regulation pattern associated to epithelial-mesenchymal transition, putatively driven by the interplay of the SP1 transcription factor and the canonical Wnt signaling pathway; the second event was the failure to overexpress a diverse set of genes coding membrane and extracellular proteins. This failure is putatively caused by a lack of activity of the AP-1 complex. It was also shown that the epithelial-mesenchymal transition was associated with the up-regulation of 5 enzymes involved in the degradation of branched chain amino acids. The suitability of silencing one of this enzymes (branched chain amino acid transaminase 2; BCAT2) with therapeutic effects was tested experimentally on the breast cancer cell line MCF-7 and primary cell culture of breast tumor (BCC), leading to lower cell proliferation. The silencing of BCAT2 did not have any significant effect on ASM and MCF10A cells, which were used as models of healthy dividing cells.

SUBMITTER: Antanaviciute I

PROVIDER: S-EPMC5552680 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Transcriptional hallmarks of cancer cell lines reveal an emerging role of branched chain amino acid catabolism.

Antanavičiūtė Ieva I Mikalayeva Valeryia V Ceslevičienė Ieva I Milašiūtė Gintarė G Skeberdis Vytenis Arvydas VA Bordel Sergio S

Scientific reports 20170810 1

A comparative analysis between cancer cell lines and healthy dividing cells was performed using data (289 microarrays and 50 RNA-seq samples) from 100 different cancer cell lines and 6 types of healthy stem cells. The analysis revealed two large-scale transcriptional events that characterize cancer cell lines. The first event was a large-scale up-regulation pattern associated to epithelial-mesenchymal transition, putatively driven by the interplay of the SP1 transcription factor and the canonica ...[more]

PMID: 28798381

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Project description:Micrococcus luteus naturally produces alkenes, unsaturated aliphatic hydrocarbons, and represents a promising host to produce hydrocarbons as constituents of biofuels and lubricants. In this work, we identify the genes for key enzymes of the branched-chain amino acid catabolism in M. luteus, whose first metabolic steps lead also to the formation of primer molecules for branched-chain fatty acid and olefin biosynthesis, and demonstrate how these genes can be used to manipulate the production of specific olefins in this organism. We constructed mutants of several gene candidates involved in the branched-chain amino acid metabolism or its regulation and investigated the resulting changes in the cellular fatty acid and olefin profiles by GC/MS. The gene cluster encoding the components of the branched-chain ?-keto acid dehydrogenase (BCKD) complex was identified by deletion and promoter exchange mutagenesis. Overexpression of the BCKD gene cluster resulted in about threefold increased olefin production whereas deletion of the cluster led to a drastic reduction in branched-chain fatty acid content and a complete loss of olefin production. The specificities of the acyl-CoA dehydrogenases of the branched amino acid degradation pathways were deduced from the fatty acid and olefin profiles of the respective deletion mutant strains. In addition, growth experiments with branched amino acids as the only nitrogen source were carried out with the mutants in order to confirm our annotations. Both the deletion mutant of the BCKD complex, responsible for the further degradation of all three branched-chain amino acids, as well as the deletion mutant of the proposed isovaleryl-CoA dehydrogenase (specific for leucine degradation) were not able to grow on leucine in contrast to the parental strain. In conclusion, our experiments allow the unambigous assignment of specific functions to the genes for key enzymes of the branched-chain amino acid metabolism of M. luteus. We also show how this knowledge can be used to engineer the isomeric composition and the chain lengths of the olefins produced by this organism.

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Transcriptional hallmarks of cancer cell lines reveal an emerging role of branched chain amino acid catabolism.

Publications

Transcriptional hallmarks of cancer cell lines reveal an emerging role of branched chain amino acid catabolism.

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