DGAT1 is a lipid metabolism oncoprotein that enables cancer cells to accumulate fatty acid while avoiding lipotoxicity
DGAT1 is a lipid metabolism oncoprotein that enables cancer cells to accumulate fatty acid while avoiding lipotoxicity
ABSTRACT 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. SIGNIFICANCEWe show that DGAT1 is a bona fide oncoprotein capable of inducing melanoma formation and co-operating with other known drivers of melanoma. DGAT1 facilitates enhanced fatty acid acquisition by melanoma cells through suppressing lipototoxicity. DGAT1 is also critical for maintaining S6K activity required for melanoma cell growth.
Wellbrock Claudia、Owen Rhys、Guerin Melissa、Lorigan Paul、Watson Joanne、Johnston Hannah、Ogden Samuel、Francavilla Chiara、Hurlstone Adam F. L.、Lloyd Gavin R.、Wilcock Daniel J.、Ferguson Harriet、Richardson Daniel A.、Fullwood Paul、Jankevics Andris、Ceol Craig、Badrock Andrew P.、Ferguson Jennifer、Southam Andrew D.、Smith Michael P.、Dunn Warwick B.
Division of Cancer Studies, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of ManchesterDivision of Cancer Studies, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of ManchesterProgram in Molecular Medicine, Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School (UMMS)Division of Cancer Studies, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of Manchester||Department of Medical Oncology, The Christie NHS Foundation TrustDivision of Molecular & Cellular Function, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of ManchesterDivision of Cancer Studies, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of ManchesterDivision of Molecular & Cellular Function, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of ManchesterDivision of Molecular & Cellular Function, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of ManchesterDivision of Infection Immunity and Respiratory Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester||Lydia Becker Institute of Immunology, The University of ManchesterSchool of Biosciences, Edgbaston, University of Birmingham||Phenome Centre Birmingham, University of BirminghamDivision of Cancer Studies, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of ManchesterDivision of Molecular & Cellular Function, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of ManchesterDivision of Cancer Studies, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of ManchesterDivision of Molecular & Cellular Function, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of ManchesterSchool of Biosciences, Edgbaston, University of Birmingham||Phenome Centre Birmingham, University of BirminghamProgram in Molecular Medicine, Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School (UMMS)Division of Molecular & Cellular Function, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of ManchesterDivision of Molecular & Cellular Function, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of ManchesterSchool of Biosciences, Edgbaston, University of Birmingham||Phenome Centre Birmingham, University of BirminghamDivision of Molecular & Cellular Function, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of ManchesterSchool of Biosciences, Edgbaston, University of Birmingham||Phenome Centre Birmingham, University of Birmingham||Institute of Metabolism and Systems Research, University of Birmingham
肿瘤学基础医学生物化学
Wellbrock Claudia,Owen Rhys,Guerin Melissa,Lorigan Paul,Watson Joanne,Johnston Hannah,Ogden Samuel,Francavilla Chiara,Hurlstone Adam F. L.,Lloyd Gavin R.,Wilcock Daniel J.,Ferguson Harriet,Richardson Daniel A.,Fullwood Paul,Jankevics Andris,Ceol Craig,Badrock Andrew P.,Ferguson Jennifer,Southam Andrew D.,Smith Michael P.,Dunn Warwick B..DGAT1 is a lipid metabolism oncoprotein that enables cancer cells to accumulate fatty acid while avoiding lipotoxicity[EB/OL].(2025-03-28)[2025-06-22].https://www.biorxiv.org/content/10.1101/2020.06.23.166603.点此复制
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