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

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

来源：Cell Metabolism, 2016, 23(1): 206-219.

DOI：10.1016/j.cmet.2015.12.004

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.

• 出版日期2016-1-12