NANOG Metabolically Reprograms Tumor-Initiating Stem-like Cells through Tumorigenic Changes in Oxidative Phosphorylation and Fatty Acid Metabolism

Chia-Lin Chen; Dinesh Babu Uthaya Kumar; Vasu Punj; Jun Xu; Linda Sher; Stanley M Tahara; Sonja Hess; Keigo Machida

doi:10.1016/j.cmet.2015.12.004

NANOG Metabolically Reprograms Tumor-Initiating Stem-like Cells through Tumorigenic Changes in Oxidative Phosphorylation and Fatty Acid Metabolism

Cell Metab. 2016 Jan 12;23(1):206-19. doi: 10.1016/j.cmet.2015.12.004. Epub 2015 Dec 24.

Authors

Chia-Lin Chen¹, Dinesh Babu Uthaya Kumar¹, Vasu Punj², Jun Xu³, Linda Sher⁴, Stanley M Tahara¹, Sonja Hess⁵, Keigo Machida⁶

Affiliations

¹ Department of Molecular Microbiology and Immunology, University of Southern California, Keck School of Medicine, Los Angeles, Los Angeles, CA 90033, USA.
² 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.
³ Department of Pathology, University of Southern California, Keck School of Medicine, Los Angeles, Los Angeles, CA 90033, USA.
⁴ Department of Surgery, University of Southern California, Keck School of Medicine, Los Angeles, Los Angeles, CA 90033, USA.
⁵ Proteome Exploration Laboratory, Beckman Institute, California Institute of Technology, Pasadena, CA 91106, USA.
⁶ 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.

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.

Keywords: HCC; NANOG; OXPHOS; fatty acid; liver; metabolic reprogramming; self-renewal; tumor-initiating stem-like cells (TICs).

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

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

Substances

E2F1 Transcription Factor
E2f1 protein, mouse
Fatty Acids
Homeodomain Proteins
Nanog Homeobox Protein
Nanog protein, mouse
Reactive Oxygen Species

Abstract

Publication types

MeSH terms

Substances

Grants and funding