期刊
CELL METABOLISM
卷 23, 期 1, 页码 206-219出版社
CELL PRESS
DOI: 10.1016/j.cmet.2015.12.004
关键词
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资金
- NIH [1R01AA018857-01, 5P30DK048522-13, P50AA11999, R24AA012885]
- American Cancer Society [IRG-58-007-48]
- CIRM [TG2-01161]
- Gordon and Betty Moore Foundation [GBMF775]
- NIH/NCI [P30 CA 014089]
- NIH/NVRR [S10]
- National Cancer Institute [P30CA014089]
- [RSG-12-177-01-MPC]
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 down-regulation 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.
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