RRC ID 36003
Author Chen CL, Uthaya Kumar DB, Punj V, Xu J, Sher L, Tahara SM, Hess S, Machida K.
Title NANOG Metabolically Reprograms Tumor-Initiating Stem-like Cells through Tumorigenic Changes in Oxidative Phosphorylation and Fatty Acid Metabolism.
Journal Cell Metab
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.
Volume 23(1)
Pages 206-19
Published 2016-1-12
DOI 10.1016/j.cmet.2015.12.004
PII S1550-4131(15)00619-1
PMID 26724859
PMC PMC4715587
MeSH Animals Carcinogenesis / metabolism* Carcinogenesis / pathology Carcinoma, Hepatocellular / metabolism* Carcinoma, Hepatocellular / pathology Cell Line, Tumor Cell Self Renewal Drug Resistance, Neoplasm E2F1 Transcription Factor / metabolism Fatty Acids Gene Expression Regulation, Neoplastic HEK293 Cells Homeodomain Proteins / physiology* Humans Lipid Metabolism Liver Neoplasms, Experimental / metabolism* Liver Neoplasms, Experimental / pathology Mitochondria, Liver / metabolism Nanog Homeobox Protein Neoplastic Stem Cells / metabolism* Oxidation-Reduction Oxidative Phosphorylation Oxidative Stress Phosphorylation Protein Processing, Post-Translational Reactive Oxygen Species / metabolism Transcriptional Activation
IF 21.567
Times Cited 110
Mice RBRC04878