NANOG Metabolically Reprograms Tumor-Initiating Stem-like Cells through Tumorigenic Changes in Oxidative Phosphorylation and Fatty Acid Metabolism.
NANOG Metabolically Reprograms Tumor-Initiating Stem-like Cells through Tumorigenic Changes in Oxidative Phosphorylation and Fatty Acid Metabolism.
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Nanog通过氧化磷酸化和脂肪酸代谢的肿瘤性变化来代谢重新编程肿瘤发射类样细胞。
DOI：
10.1016/j.cmet.2015.12.004
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发表时间：
2016-01-12
期刊：
影响因子：
29
通讯作者：
Machida K
中科院分区：
文献类型：
--
作者：
Chen CL;Uthaya Kumar DB;Punj V;Xu J;Sher L;Tahara SM;Hess S;Machida K
干细胞标记物如NANOG与多种癌症有关;然而，NANOG对癌症发病机制的功能贡献仍不清楚。在这里，我们表明Toll样受体4（TLR 4）信号磷酸化E2 F1反式激活NANOG。Nanog的下调减少了肿瘤进展。NANOG ChIP-seq鉴定了与NANOG依赖性线粒体代谢途径相关的基因，以维持肿瘤起始干细胞（TIC）。NANOG在线粒体代谢重编程中的因果作用是通过抑制氧化磷酸化（OXPHOS），减少线粒体ROS的产生和激活自我更新和耐药性所需的脂肪酸氧化（FAO）来实现的。OXPHOS活性的恢复和FAO的抑制使得TIC对标准护理化疗药物索拉非尼敏感。这项研究提供了对NANOG介导的TIC生成、肿瘤发生和由于线粒体功能的代谢重编程引起的化学抗性的机制的见解。
Stem cell markers such as NANOG have been implicated in various cancers; however, the functional contribution of NANOG to cancer pathogenesis has remained unclear. Here, we show that Toll-like receptor 4 (TLR4) signaling phosphorylates E2F1 to transactivate NANOG. Down-regulation of Nanog reduces tumor progression. NANOG ChIP-seq identified genes associated with NANOG-dependent mitochondrial metabolic pathways to maintain tumor-initiating stem-like cells (TICs). The causal roles of NANOG in mitochondrial metabolic reprogramming occurred through the inhibition of oxidative phosphorylation (OXPHOS) with decreased production of mitochondrial ROS and activation of fatty acid oxidation (FAO), which was required for self-renewal and drug resistance. Restoration of OXPHOS activity and inhibition of FAO rendered TICs susceptible to a standard care chemotherapy drug, sorafenib. This study provides insights into the mechanisms of NANOG-mediated generation of TICs, tumorigenesis and chemo-resistance due to metabolic reprograming of mitochondrial functions.