Yeh Da-Wei, Liu Cheng, Hernandez Juan Carlos, Tahara Stanley M, Tsukamoto Hidekazu, Machida Keigo
Departments of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA.
Department of Pathology; University of Southern California, Los Angeles, CA 90033, USA.
iScience. 2023 Jun 7;26(7):107035. doi: 10.1016/j.isci.2023.107035. eCollection 2023 Jul 21.
The synergistic effect of alcohol and HCV mediated through TLR4 signaling transactivates NANOG, a pluripotency transcription factor important for the stemness of tumor-initiating stem-like cells (TICs). NANOG together with the PRC2 complex suppresses expression of oxidative phosphorylation (OXPHOS) genes to generate TICs. The phosphodegron sequence PEST domain of NANOG binds EED to stabilize NANOG protein by blocking E3 ligase recruitment and proteasome-dependent degradation, while the tryptophan-rich domain of NANOG binds EZH2 and SUZ12. Human ARID1A gene loss results in the resistance to combined FAO and PRC2 inhibition therapies due to reduction of mitochondrial ROS levels. CRISPR-Cas9-mediated knockout and/or constitutively active driver mutations promoted tumor development in humanized FRG HCC mouse models, in which use of an interface inhibitor antagonizing PRC2-NANOG binding and/or FAO inhibitor blocked tumor growth. Together, the PRC2-NANOG interaction becomes a new drug target for HCC via inducing differentiation-related genes, destabilizing NANOG protein, and suppressing NANOG activity.
酒精与丙型肝炎病毒（HCV）通过Toll样受体4（TLR4）信号传导产生的协同效应可反式激活NANOG，NANOG是一种对肿瘤起始干细胞样细胞（TIC）干性至关重要的多能性转录因子。NANOG与多梳蛋白2（PRC2）复合物共同抑制氧化磷酸化（OXPHOS）基因的表达以产生TIC。NANOG的磷酸化降解序列PEST结构域与胚胎外胚层发育蛋白（EED）结合，通过阻止E3连接酶募集和蛋白酶体依赖性降解来稳定NANOG蛋白，而NANOG富含色氨酸的结构域与EZH2和SUZ12结合。人类AT丰富互作结构域1A（ARID1A）基因缺失导致对联合脂肪酸氧化（FAO）和PRC2抑制疗法产生抗性，这是由于线粒体活性氧（ROS）水平降低所致。在人源化FRG肝癌小鼠模型中，CRISPR-Cas9介导的基因敲除和/或组成型活性驱动突变促进了肿瘤发展，其中使用拮抗PRC2-NANOG结合的界面抑制剂和/或FAO抑制剂可阻断肿瘤生长。总之，PRC2-NANOG相互作用通过诱导分化相关基因、使NANOG蛋白不稳定并抑制NANOG活性，成为肝癌的一个新药物靶点。
