Multi-omics after O-GlcNAc alteration identified cellular processes promoting aneuploidy after loss of O-GlcNAc transferase.

Autor:	Boyd SS; Department of Biostatistics and Data Science, University of Kansas Medical Center, Kansas City, KS, USA., Robarts DR; Department of Pharmacology, Toxicology and Therapeutics, Kansas City, KS, USA., Nguyen K; Department of Biochemistry, University of Kansas Medical Center, Kansas City, KS, USA., Villar M; Department of Biochemistry, University of Kansas Medical Center, Kansas City, KS, USA., Alghusen IM; Department of Biochemistry, University of Kansas Medical Center, Kansas City, KS, USA., Kotulkar M; Department of Pharmacology, Toxicology and Therapeutics, Kansas City, KS, USA., Denson A; Department of Biochemistry, University of Kansas Medical Center, Kansas City, KS, USA., Fedosyuk H; Department of Biochemistry, University of Kansas Medical Center, Kansas City, KS, USA., Whelan SA; Department of Chemistry, Boston University, Boston, MA, USA; Precision Biomarker Laboratories, Cedars-Sinai Medical Center, Beverly Hills, CA, USA., Lee NCY; Department of Chemistry, Boston University, Boston, MA, USA; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA., Hanover J; Laboratory of Cell Biochemistry and Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA., Dias WB; Federal University of Rio De Janeiro, Rio De Janeiro, Brazil., Tan EP; Department of Biochemistry, University of Kansas Medical Center, Kansas City, KS, USA; Department of Chemistry, Neurodegeneration New Medicines Center, and the Skaggs Institute of Chemical Biology, The Scripps Research Institute, La Jolla, CA, USA., McGreal SR; Department of Pharmacology, Toxicology and Therapeutics, Kansas City, KS, USA; XenoTech, A BioIVT Company, Kansas City, KS, USA., Artigues A; Department of Biochemistry, University of Kansas Medical Center, Kansas City, KS, USA., Swerdlow RH; Department of Biochemistry, University of Kansas Medical Center, Kansas City, KS, USA; Department of Neurology, University of Kansas Medical Center, Kansas City, KS, USA; University of Kansas Alzheimer's Disease Research Center, KS, USA., Thompson JA; Department of Biostatistics and Data Science, University of Kansas Medical Center, Kansas City, KS, USA; University of Kansas Cancer Center, Kansas City, KS, USA., Apte U; Department of Pharmacology, Toxicology and Therapeutics, Kansas City, KS, USA., Slawson C; Department of Biochemistry, University of Kansas Medical Center, Kansas City, KS, USA; University of Kansas Alzheimer's Disease Research Center, KS, USA; University of Kansas Cancer Center, Kansas City, KS, USA. Electronic address: cslawson@kumc.edu.
Jazyk:	angličtina
Zdroj:	Molecular metabolism [Mol Metab] 2024 Dec; Vol. 90, pp. 102060. Date of Electronic Publication: 2024 Oct 29.
DOI:	10.1016/j.molmet.2024.102060
Abstrakt:	Objective: Pharmacologic or genetic manipulation of O-GlcNAcylation, an intracellular, single sugar post-translational modification, are difficult to interpret due to the pleotropic nature of O-GlcNAc and the vast signaling pathways it regulates. Method: To address the pleotropic nature of O-GlcNAc, we employed either OGT (O-GlcNAc transferase), OGA (O-GlcNAcase) liver knockouts, or pharmacological inhibition of OGA coupled with multi-Omics analysis and bioinformatics. Results: We identified numerous genes, proteins, phospho-proteins, or metabolites that were either inversely or equivalently changed between conditions. Moreover, we identified pathways in OGT knockout samples associated with increased aneuploidy. To test and validate these pathways, we induced liver growth in OGT knockouts by partial hepatectomy. OGT knockout livers showed a robust aneuploidy phenotype with disruptions in mitosis, nutrient sensing, protein metabolism/amino acid metabolism, stress response, and HIPPO signaling demonstrating how OGT is essential in controlling aneuploidy pathways. Conclusion: These data show how a multi-Omics platform can disentangle the pleotropic nature of O-GlcNAc to discern how OGT fine-tunes multiple cellular pathways involved in aneuploidy. Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Chad Slawson reports financial support was provided by National Institutes of Health. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (Copyright © 2024 The Author(s). Published by Elsevier GmbH.. All rights reserved.)
Databáze:	MEDLINE
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