Dataset Information

Chaperome Networks - Redundancy and Implications for Cancer Treatment.

ABSTRACT: The chaperome is a large family of proteins composed of chaperones, co-chaperones and a multitude of other factors. Elegant studies in yeast and other organisms have paved the road to how we currently understand the complex organization of this large family into protein networks. The goal of this chapter is to provide an overview of chaperome networks in cancer cells, with a focus on two cellular states defined by chaperome network organization. One state characterized by chaperome networks working in isolation and with little overlap, contains global chaperome networks resembling those of normal, non-transformed, cells. We propose that in this state, redundancy in chaperome networks results in a tumor type unamenable for single-agent chaperome therapy. The second state comprises chaperome networks interconnected in response to cellular stress, such as MYC hyperactivation. This is a state where no redundant pathways can be deployed, and is a state of vulnerability, amenable for chaperome therapy. We conclude by proposing a change in how we discover and implement chaperome inhibitor strategies, and suggest an approach to chaperome therapy where the properties of chaperome networks, rather than genetics or client proteins, are used in chaperome inhibitor implementation.

SUBMITTER: Yan P

PROVIDER: S-EPMC7279512 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Chaperome Networks - Redundancy and Implications for Cancer Treatment.

Yan Pengrong P Wang Tai T Guzman Monica L ML Peter Radu I RI Chiosis Gabriela G

Advances in experimental medicine and biology 20200101

The chaperome is a large family of proteins composed of chaperones, co-chaperones and a multitude of other factors. Elegant studies in yeast and other organisms have paved the road to how we currently understand the complex organization of this large family into protein networks. The goal of this chapter is to provide an overview of chaperome networks in cancer cells, with a focus on two cellular states defined by chaperome network organization. One state characterized by chaperome networks work ...[more]

PMID: 32297213

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Project 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 (Pro2) 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.

Dataset Information

Chaperome Networks - Redundancy and Implications for Cancer Treatment.

Publications

Chaperome Networks - Redundancy and Implications for Cancer Treatment.

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