福克斯A1
癌变
癌症研究
肝癌
基因剔除小鼠
生物
遗传学
乳腺癌
癌症
肝细胞癌
受体
作者
Bing Gao,Xueji Wu,Lang Bu,Qiwei Jiang,Lei Wang,Hai-Ning Liu,Xiaomei Zhang,Yuanzhong Wu,Xiao-Xing Li,Jingting Li,Ying Liang,Lixia Xu,Wei Xie,Jianping Guo
出处
期刊:Science Advances
[American Association for the Advancement of Science (AAAS)]
日期:2024-02-09
卷期号:10 (6)
标识
DOI:10.1126/sciadv.adk2285
摘要
Physiologically, FoxA1 plays a key role in liver differentiation and development, and pathologically exhibits an oncogenic role in prostate and breast cancers. However, its role and upstream regulation in liver tumorigenesis remain unclear. Here, we demonstrate that FoxA1 acts as a tumor suppressor in liver cancer. Using a CRISPR-based kinome screening approach, noncanonical inflammatory kinase IKBKE has been identified to inhibit FoxA1 transcriptional activity. Notably, IKBKE directly binds to and phosphorylates FoxA1 to reduce its complex formation and DNA interaction, leading to elevated hepatocellular malignancies. Nonphosphorylated mimic Foxa1 knock-in mice markedly delay liver tumorigenesis in hydrodynamic transfection murine models, while phospho-mimic Foxa1 knock-in phenocopy Foxa1 knockout mice to exhibit developmental defects and liver inflammation. Notably, Ikbke knockout delays diethylnitrosamine (DEN)-induced mouse liver tumor development. Together, our findings not only reveal FoxA1 as a bona fide substrate and negative nuclear effector of IKBKE in hepatocellular carcinioma (HCC) but also provide a promising strategy to target IKBEK for HCC therapy.
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