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A systematic atlas of chaperome deregulation topologies across the human cancer landscape
Proteome balance is safeguarded by the proteostasis network (PN), an intricately regulated network of conserved processes that evolved to maintain native function of the diverse ensemble of protein species, ensuring cellular and organismal health. Proteostasis imbalances and collapse are implicated...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5766242/ https://www.ncbi.nlm.nih.gov/pubmed/29293508 http://dx.doi.org/10.1371/journal.pcbi.1005890 |
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author | Hadizadeh Esfahani, Ali Sverchkova, Angelina Saez-Rodriguez, Julio Schuppert, Andreas A. Brehme, Marc |
author_facet | Hadizadeh Esfahani, Ali Sverchkova, Angelina Saez-Rodriguez, Julio Schuppert, Andreas A. Brehme, Marc |
author_sort | Hadizadeh Esfahani, Ali |
collection | PubMed |
description | Proteome balance is safeguarded by the proteostasis network (PN), an intricately regulated network of conserved processes that evolved to maintain native function of the diverse ensemble of protein species, ensuring cellular and organismal health. Proteostasis imbalances and collapse are implicated in a spectrum of human diseases, from neurodegeneration to cancer. The characteristics of PN disease alterations however have not been assessed in a systematic way. Since the chaperome is among the central components of the PN, we focused on the chaperome in our study by utilizing a curated functional ontology of the human chaperome that we connect in a high-confidence physical protein-protein interaction network. Challenged by the lack of a systems-level understanding of proteostasis alterations in the heterogeneous spectrum of human cancers, we assessed gene expression across more than 10,000 patient biopsies covering 22 solid cancers. We derived a novel customized Meta-PCA dimension reduction approach yielding M-scores as quantitative indicators of disease expression changes to condense the complexity of cancer transcriptomics datasets into quantitative functional network topographies. We confirm upregulation of the HSP90 family and also highlight HSP60s, Prefoldins, HSP100s, ER- and mitochondria-specific chaperones as pan-cancer enriched. Our analysis also reveals a surprisingly consistent strong downregulation of small heat shock proteins (sHSPs) and we stratify two cancer groups based on the preferential upregulation of ATP-dependent chaperones. Strikingly, our analyses highlight similarities between stem cell and cancer proteostasis, and diametrically opposed chaperome deregulation between cancers and neurodegenerative diseases. We developed a web-based Proteostasis Profiler tool (Pro(2)) enabling intuitive analysis and visual exploration of proteostasis disease alterations using gene expression data. Our study showcases a comprehensive profiling of chaperome shifts in human cancers and sets the stage for a systematic global analysis of PN alterations across the human diseasome towards novel hypotheses for therapeutic network re-adjustment in proteostasis disorders. |
format | Online Article Text |
id | pubmed-5766242 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-57662422018-01-26 A systematic atlas of chaperome deregulation topologies across the human cancer landscape Hadizadeh Esfahani, Ali Sverchkova, Angelina Saez-Rodriguez, Julio Schuppert, Andreas A. Brehme, Marc PLoS Comput Biol Research Article Proteome balance is safeguarded by the proteostasis network (PN), an intricately regulated network of conserved processes that evolved to maintain native function of the diverse ensemble of protein species, ensuring cellular and organismal health. Proteostasis imbalances and collapse are implicated in a spectrum of human diseases, from neurodegeneration to cancer. The characteristics of PN disease alterations however have not been assessed in a systematic way. Since the chaperome is among the central components of the PN, we focused on the chaperome in our study by utilizing a curated functional ontology of the human chaperome that we connect in a high-confidence physical protein-protein interaction network. Challenged by the lack of a systems-level understanding of proteostasis alterations in the heterogeneous spectrum of human cancers, we assessed gene expression across more than 10,000 patient biopsies covering 22 solid cancers. We derived a novel customized Meta-PCA dimension reduction approach yielding M-scores as quantitative indicators of disease expression changes to condense the complexity of cancer transcriptomics datasets into quantitative functional network topographies. We confirm upregulation of the HSP90 family and also highlight HSP60s, Prefoldins, HSP100s, ER- and mitochondria-specific chaperones as pan-cancer enriched. Our analysis also reveals a surprisingly consistent strong downregulation of small heat shock proteins (sHSPs) and we stratify two cancer groups based on the preferential upregulation of ATP-dependent chaperones. Strikingly, our analyses highlight similarities between stem cell and cancer proteostasis, and diametrically opposed chaperome deregulation between cancers and neurodegenerative diseases. We developed a web-based Proteostasis Profiler tool (Pro(2)) enabling intuitive analysis and visual exploration of proteostasis disease alterations using gene expression data. Our study showcases a comprehensive profiling of chaperome shifts in human cancers and sets the stage for a systematic global analysis of PN alterations across the human diseasome towards novel hypotheses for therapeutic network re-adjustment in proteostasis disorders. Public Library of Science 2018-01-02 /pmc/articles/PMC5766242/ /pubmed/29293508 http://dx.doi.org/10.1371/journal.pcbi.1005890 Text en © 2018 Hadizadeh Esfahani et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Hadizadeh Esfahani, Ali Sverchkova, Angelina Saez-Rodriguez, Julio Schuppert, Andreas A. Brehme, Marc A systematic atlas of chaperome deregulation topologies across the human cancer landscape |
title | A systematic atlas of chaperome deregulation topologies across the human cancer landscape |
title_full | A systematic atlas of chaperome deregulation topologies across the human cancer landscape |
title_fullStr | A systematic atlas of chaperome deregulation topologies across the human cancer landscape |
title_full_unstemmed | A systematic atlas of chaperome deregulation topologies across the human cancer landscape |
title_short | A systematic atlas of chaperome deregulation topologies across the human cancer landscape |
title_sort | systematic atlas of chaperome deregulation topologies across the human cancer landscape |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5766242/ https://www.ncbi.nlm.nih.gov/pubmed/29293508 http://dx.doi.org/10.1371/journal.pcbi.1005890 |
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