MYC disrupts transcriptional and metabolic circadian oscillations in cancer and promotes enhanced biosynthesis.

Autor: Cazarin J; Department of Biomedical Genetics, University of Rochester School of Medicine and Dentistry, Rochester, New York, United States of America., DeRollo RE; Department of Biomedical Genetics, University of Rochester School of Medicine and Dentistry, Rochester, New York, United States of America., Shahidan SNABA; Department of Biomedical Genetics, University of Rochester School of Medicine and Dentistry, Rochester, New York, United States of America., Burchett JB; Department of Biomedical Genetics, University of Rochester School of Medicine and Dentistry, Rochester, New York, United States of America., Mwangi D; Department of Biomedical Genetics, University of Rochester School of Medicine and Dentistry, Rochester, New York, United States of America., Krishnaiah S; Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.; Institute of Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.; Chronobiology and Sleep Institute, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America., Hsieh AL; The Wistar Institute, Philadelphia, Pennsylvania, United States of America., Walton ZE; The Wistar Institute, Philadelphia, Pennsylvania, United States of America., Brooks R; The Wistar Institute, Philadelphia, Pennsylvania, United States of America., Mello SS; Department of Biomedical Genetics, University of Rochester School of Medicine and Dentistry, Rochester, New York, United States of America.; Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, United States of America., Weljie AM; Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.; Institute of Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.; Chronobiology and Sleep Institute, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America., Dang CV; Ludwig Institute for Cancer Research, New York, New York, United States of America.; The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.; Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Maryland, United States of America., Altman BJ; Department of Biomedical Genetics, University of Rochester School of Medicine and Dentistry, Rochester, New York, United States of America.; Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, United States of America.
Jazyk: angličtina
Zdroj: PLoS genetics [PLoS Genet] 2023 Aug 28; Vol. 19 (8), pp. e1010904. Date of Electronic Publication: 2023 Aug 28 (Print Publication: 2023).
DOI: 10.1371/journal.pgen.1010904
Abstrakt: The molecular circadian clock, which controls rhythmic 24-hour oscillation of genes, proteins, and metabolites in healthy tissues, is disrupted across many human cancers. Deregulated expression of the MYC oncoprotein has been shown to alter expression of molecular clock genes, leading to a disruption of molecular clock oscillation across cancer types. It remains unclear what benefit cancer cells gain from suppressing clock oscillation, and how this loss of molecular clock oscillation impacts global gene expression and metabolism in cancer. We hypothesized that MYC or its paralog N-MYC (collectively termed MYC herein) suppress oscillation of gene expression and metabolism to upregulate pathways involved in biosynthesis in a static, non-oscillatory fashion. To test this, cells from distinct cancer types with inducible MYC were examined, using time-series RNA-sequencing and metabolomics, to determine the extent to which MYC activation disrupts global oscillation of genes, gene expression pathways, and metabolites. We focused our analyses on genes, pathways, and metabolites that changed in common across multiple cancer cell line models. We report here that MYC disrupted over 85% of oscillating genes, while instead promoting enhanced ribosomal and mitochondrial biogenesis and suppressed cell attachment pathways. Notably, when MYC is activated, biosynthetic programs that were formerly circadian flipped to being upregulated in an oscillation-free manner. Further, activation of MYC ablates the oscillation of nutrient transporter proteins while greatly upregulating transporter expression, cell surface localization, and intracellular amino acid pools. Finally, we report that MYC disrupts metabolite oscillations and the temporal segregation of amino acid metabolism from nucleotide metabolism. Our results demonstrate that MYC disruption of the molecular circadian clock releases metabolic and biosynthetic processes from circadian control, which may provide a distinct advantage to cancer cells.
Competing Interests: The authors have declared that no competing interests exist.
(Copyright: © 2023 Cazarin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
Databáze: MEDLINE
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