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- W2015479767 abstract "Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CAStem cell markers such as Nanog have been implicated in various cancer, but whether they are functionally contributing to cancer pathogenesis has remained unclear. We previously reported that Toll-like receptor 4 (TLR4) signaling regulated NANOG expression in liver cancers (Chen et al., J. Clin. Inv., 2013). Here, we determined novel targets of NANOG in CD133+CD49f+ tumor-initiating cells (TICs) from patient and mouse models of hepatocellular carcinoma (HCC) using genome-wide NANOG-binding site analysis (ChIP-seq). Silencing NANOG inhibits tumor development in HCC mouse models and genesis of TICs as alcohol/obesity-associated increase of serum bacterial products activates TLR4 signaling. To determine novel targets of NANOG in TICs isolated from several HCC models, ChIP-seq in TICs was performed. NANOG binds genes of oxidative phosphorylation and β-oxidation in mitochondria. Silencing NANOG promotes oxidative phosphorylation and β-oxidation, indicating that NANOG is a suppressor of mitochondria-mediated energy production. We identified the TLR4-NANOG oncogenic pathway in the genesis of TICs and liver tumor in HCC mouse models, including alcohol/high-fat-diet-fed hepatitis C virus (HCV) transgenic mice, DEN/phenobarbtal-treated and Spnb2+/- mice. We identified the stimulation of TLR4 transactivates Nanog through E2F1 phosphorylation at serine residues 332/336 and generates TICs, leading to development of liver tumors. Metabolomic analysis demonstrates metabolic reprogramming in TICs through NANOG. Reduction of NANOG expression resulted in an improved cellular energy balance, including reduction of the glycolysis pathway, increased fatty acid consumption and greater uptake of amino acids. The improved energy status is linked to a shift away from glycolysis and a greater reliance on fatty acid β-oxidation and amino acid anaplerosis. Taken together, these results suggest that NANOG-mediated metabolic reprogramming through suppression of mitochondria function in both experimental and clinical HCC downstream of TLR4/NANOG generates TICs and drives liver tumorigenesis.Citation Format: Chia-Lin Chen, Vasu Punj, Linda Sher, Lydia Petrovic, Keigo Machida. NANOG represses mitochondrial energy production and promotes fatty acid synthesis to promote self-renewal in tumor-initiating cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4794. doi:10.1158/1538-7445.AM2014-4794" @default.
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- W2015479767 date "2014-09-30" @default.
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- W2015479767 title "Abstract 4794: NANOG represses mitochondrial energy production and promotes fatty acid synthesis to promote self-renewal in tumor-initiating cells" @default.
- W2015479767 doi "https://doi.org/10.1158/1538-7445.am2014-4794" @default.
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