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

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

Author information

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)

PMID:
26724859
PMCID:
PMC4715587
DOI:
10.1016/j.cmet.2015.12.004
[Indexed for MEDLINE]
Free PMC Article

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