Dataset Information

Chaperome heterogeneity and its implications for cancer study and treatment.

ABSTRACT: The chaperome is the collection of proteins in the cell that carry out molecular chaperoning functions. Changes in the interaction strength between chaperome proteins lead to an assembly that is functionally and structurally distinct from each constituent member. In this review, we discuss the epichaperome, the cellular network that forms when the chaperome components of distinct chaperome machineries come together as stable, functionally integrated, multimeric complexes. In tumors, maintenance of the epichaperome network is vital for tumor survival, rendering them vulnerable to therapeutic interventions that target critical epichaperome network components. We discuss how the epichaperome empowers an approach for precision medicine cancer trials where a new target, biomarker, and relevant drug candidates can be correlated and integrated. We introduce chemical biology methods to investigate the heterogeneity of the chaperome in a given cellular context. Lastly, we discuss how ligand-protein binding kinetics are more appropriate than equilibrium binding parameters to characterize and unravel chaperome targeting in cancer and to gauge the selectivity of ligands for specific tumor-associated chaperome pools.

SUBMITTER: Wang T

PROVIDER: S-EPMC6369301 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Chaperome heterogeneity and its implications for cancer study and treatment.

Wang Tai T Rodina Anna A Dunphy Mark P MP Corben Adriana A Modi Shanu S Guzman Monica L ML Gewirth Daniel T DT Chiosis Gabriela G

The Journal of biological chemistry 20181108 6

The chaperome is the collection of proteins in the cell that carry out molecular chaperoning functions. Changes in the interaction strength between chaperome proteins lead to an assembly that is functionally and structurally distinct from each constituent member. In this review, we discuss the epichaperome, the cellular network that forms when the chaperome components of distinct chaperome machineries come together as stable, functionally integrated, multimeric complexes. In tumors, maintenance ...[more]

PMID: 30409908

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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 heterogeneity and its implications for cancer study and treatment.

Publications

Chaperome heterogeneity and its implications for cancer study and treatment.

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