title: Metabolic reprogramming during TGFβ1-induced epithelial-to-mesenchymal transition.
abstract: Metastatic progression, including extravasation and micrometastatic outgrowth, is the main cause of cancer patient death. Recent studies suggest that cancer cells reprogram their metabolism to support increased proliferation through increased glycolysis and biosynthetic activities, including lipogenesis pathways. However, metabolic changes during metastatic progression, including alterations in regulatory gene expression, remain undefined. We show that transforming growth factor beta 1 (TGFβ1)-induced epithelial-to-mesenchymal transition (EMT) is accompanied by coordinately reduced enzyme expression required to convert glucose into fatty acids, and concomitant enhanced respiration. Overexpressed Snail1, a transcription factor mediating TGFβ1-induced EMT, was sufficient to suppress carbohydrate-responsive-element-binding protein (ChREBP, a master lipogenic regulator), and fatty acid synthase (FASN), its effector lipogenic gene. Stable FASN knockdown was sufficient to induce EMT, stimulate migration and extravasation in vitro. FASN silencing enhanced lung metastasis and death in vivo. These data suggest that a metabolic transition that suppresses lipogenesis and favors energy production is an essential component of TGFβ1-induced EMT and metastasis.
authors.affiliation: Children's Medical Center Research Institute, Dallas, TX, USA.
authors.forename: L
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Department of Pharmacology and Radiation Oncology, UT Southwestern Medical Center, Dallas, TX, USA.
authors.forename: L
authors.initials: L
authors.lastname: Xiao
authors.affiliation: 1] Department of Pharmacology and Radiation Oncology, UT Southwestern Medical Center, Dallas, TX, USA [2] Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA.
authors.forename: H
authors.initials: H
authors.lastname: Sugiura
authors.affiliation: Department of Pharmacology and Radiation Oncology, UT Southwestern Medical Center, Dallas, TX, USA.
authors.forename: X
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USA.
authors.forename: A
authors.initials: A
authors.lastname: Ali
authors.affiliation: 1] Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA [2] Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Kuro-o
authors.affiliation: Children's Medical Center Research Institute, Dallas, TX, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Deberardinis
authors.affiliation: Department of Pharmacology and Radiation Oncology, UT Southwestern Medical Center, Dallas, TX, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Boothman
mesh_terms: D000818:Animals; D050260:Carbohydrate Metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D004794:Enzyme Repression; D058750:Epithelial-Mesenchymal Transition; D054890:Fatty Acid Synthase, Type I / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D050356:Lipid Metabolism; D008175:Lung Neoplasms / Q000378:metabolism / Q000556:secondary; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000502:physiology; D053773:Transforming Growth Factor beta1 / Q000502:physiology*
chemical_list: C000604407:SNAI1 protein, human; C000604429:Snai1 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; C518729:FASN protein, human; D054890:Fatty Acid Synthase, Type I