| RRC ID |
36003
|
| 著者 |
Chen CL, Uthaya Kumar DB, Punj V, Xu J, Sher L, Tahara SM, Hess S, Machida K.
|
| タイトル |
NANOG Metabolically Reprograms Tumor-Initiating Stem-like Cells through Tumorigenic Changes in Oxidative Phosphorylation and Fatty Acid Metabolism.
|
| ジャーナル |
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.
|
| 巻・号 |
23(1)
|
| ページ |
206-19
|
| 公開日 |
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
|
| 引用数 |
110
|
|
WOS 分野
|
ENDOCRINOLOGY & METABOLISM
CELL BIOLOGY
|
| リソース情報 |
| 実験動物マウス |
RBRC04878 |
