title: NANOG Metabolically Reprograms Tumor-Initiating Stem-like Cells through Tumorigenic Changes in Oxidative Phosphorylation and Fatty Acid Metabolism.
abstract: Stem cell markers, including NANOG, have been implicated in various cancers; however, the functional contribution of NANOG to cancer pathogenesis has remained unclear. Here, we show that NANOG is induced by Toll-like receptor 4 (TLR4) signaling via phosphorylation of E2F1 and that downregulation of Nanog slows down hepatocellular carcinoma (HCC) progression induced by alcohol western diet and hepatitis C virus protein in mice. NANOG ChIP-seq analyses reveal that NANOG regulates the expression of genes involved in mitochondrial metabolic pathways required to maintain tumor-initiating stem-like cells (TICs). NANOG represses mitochondrial oxidative phosphorylation (OXPHOS) genes, as well as ROS generation, and activates fatty acid oxidation (FAO) to support TIC self-renewal and drug resistance. Restoration of OXPHOS activity and inhibition of FAO renders TICs susceptible to a standard care chemotherapy drug for HCC, sorafenib. This study provides insights into the mechanisms of NANOG-mediated generation of TICs, tumorigenesis, and chemoresistance through reprogramming of mitochondrial metabolism.
authors.affiliation: Department of Molecular Microbiology and Immunology, University of Southern California, Keck School of Medicine, Los Angeles, Los Angeles, CA 90033, USA.
authors.forename: Chia-Lin
authors.initials: CL
authors.lastname: Chen
authors.affiliation: Department of Molecular Microbiology and Immunology, University of Southern California, Keck School of Medicine, Los Angeles, Los Angeles, CA 90033, USA.
authors.forename: Dinesh Babu
authors.initials: DB
authors.lastname: Uthaya Kumar
authors.affiliation: Department of Medicine, University of Southern California, Keck School of Medicine, Los Angeles, Los Angeles, CA 90033, USA; Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Vasu
authors.initials: V
authors.lastname: Punj
authors.affiliation: Department of Pathology, University of Southern California, Keck School of Medicine, Los Angeles, Los Angeles, CA 90033, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Surgery, University of Southern California, Keck School of Medicine, Los Angeles, Los Angeles, CA 90033, USA.
authors.forename: Linda
authors.initials: L
authors.lastname: Sher
authors.affiliation: Department of Molecular Microbiology and Immunology, University of Southern California, Keck School of Medicine, Los Angeles, Los Angeles, CA 90033, USA.
authors.forename: Stanley M
authors.initials: SM
authors.lastname: Tahara
authors.affiliation: Proteome Exploration Laboratory, Beckman Institute, California Institute of Technology, Pasadena, CA 91106, USA.
authors.forename: Sonja
authors.initials: S
authors.lastname: Hess
authors.affiliation: Department of Molecular Microbiology and Immunology, University of Southern California, Keck School of Medicine, Los Angeles, Los Angeles, CA 90033, USA; Southern California Research Center for ALPD and Cirrhosis, Los Angeles, CA 90033, USA. Electronic address: keigo.machida@med.usc.edu.
authors.forename: Keigo
authors.initials: K
authors.lastname: Machida
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism* / Q000473:pathology; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D000066673:Cell Self Renewal; D019008:Drug Resistance, Neoplasm; D050687:E2F1 Transcription Factor / Q000378:metabolism; D005227:Fatty Acids; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000502:physiology*; D006801:Humans; D050356:Lipid Metabolism; D008114:Liver Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology; D008930:Mitochondria, Liver / Q000378:metabolism; D000071317:Nanog Homeobox Protein; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D010084:Oxidation-Reduction; D010085:Oxidative Phosphorylation; D018384:Oxidative Stress; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017382:Reactive Oxygen Species / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D050687:E2F1 Transcription Factor; C493754:E2f1 protein, mouse; D005227:Fatty Acids; D018398:Homeodomain Proteins; D000071317:Nanog Homeobox Protein; C475540:Nanog protein, mouse; D017382:Reactive Oxygen Species
keywords: HCC; NANOG; OXPHOS; fatty acid; liver; metabolic reprogramming; self-renewal; tumor-initiating stem-like cells (TICs)