Program in Molecular Medicine; Department of Molecular, Cell and Cancer Biology
Amino Acids, Peptides, and Proteins | Biochemical Phenomena, Metabolism, and Nutrition | Cancer Biology | Cellular and Molecular Physiology | Enzymes and Coenzymes | Lipids
Dysregulated cellular metabolism is a hallmark of cancer. As yet, few druggable oncoproteins directly responsible for this hallmark have been identified. Increased fatty acid acquisition allows cancer cells to meet their membrane biogenesis, ATP, and signaling needs. Excess fatty acids suppress growth factor signaling and cause oxidative stress in non-transformed cells, but surprisingly not in cancer cells. Molecules underlying this cancer adaptation may provide new drug targets. Here, we identify Diacylglycerol O-acyltransferase 1 (DGAT1), an enzyme integral to triacylglyceride synthesis and lipid droplet formation, as a frequently up-regulated oncoprotein allowing cancer cells to tolerate excess fatty acids. DGAT1 over-expression alone induced melanoma in zebrafish melanocytes, and co-operated with oncogenic BRAF or NRAS for more rapid melanoma formation. Mechanistically, DGAT1 stimulated melanoma cell growth through sustaining mTOR kinase–S6 kinase signaling and suppressed cell death by tempering fatty acid oxidation, thereby preventing accumulation of reactive oxygen species including lipid peroxides.
cancer biology, metabolism, oncoproteins, fatty acids, lipotoxicity
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The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It is made available under a CC-BY-NC-ND 4.0 International license.
DOI of Published Version
bioRxiv 2020.06.23.166603; doi: https://doi.org/10.1101/2020.06.23.166603. Link to preprint on bioRxiv service.
Wilcock DJ, Kasheta M, Ceol CJ. (2020). DGAT1 is a lipid metabolism oncoprotein that enables cancer cells to accumulate fatty acid while avoiding lipotoxicity. University of Massachusetts Medical School Faculty Publications. https://doi.org/10.1101/2020.06.23.166603. Retrieved from https://escholarship.umassmed.edu/faculty_pubs/1780
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This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.
Amino Acids, Peptides, and Proteins Commons, Biochemical Phenomena, Metabolism, and Nutrition Commons, Cancer Biology Commons, Cellular and Molecular Physiology Commons, Enzymes and Coenzymes Commons, Lipids Commons