Atypical inflammatory kinase IKBKE phosphorylates and inactivates FoxA1 to promote liver tumorigenesis

• DOI: 10.1126/sciadv.adk2285
• Publication Date: 2024-02-07T19:36:41Z
• Authors: Bing Gao; Xueji Wu; Lang Bu; Qiwei Jiang; Lei Wang; Haining Liu; Xiaomei Zhang; Yuanzhong Wu; Xiaoxing Li; Jingting Li; Ying Liang; Lixia Xu; Wei Xie; Jianping Guo
• Keywords: FOXA1; Liver Cancer; Knockout mouse

Physiologically, FoxA1 plays a key role in liver differentiation and development, pathologically exhibits an oncogenic prostate breast cancers. However, its upstream regulation tumorigenesis remain unclear. Here, we demonstrate that acts as tumor suppressor cancer. Using CRISPR-based kinome screening approach, noncanonical inflammatory kinase IKBKE has been identified to inhibit transcriptional activity. Notably, directly binds phosphorylates reduce complex formation DNA interaction, leading elevated hepatocellular malignancies. Nonphosphorylated mimic Foxa1 knock-in mice markedly delay hydrodynamic transfection murine models, while phospho-mimic phenocopy knockout exhibit developmental defects inflammation. Ikbke delays diethylnitrosamine (DEN)-induced mouse development. Together, our findings not only reveal bona fide substrate negative nuclear effector of carcinioma (HCC) but also provide promising strategy target IKBEK for HCC therapy.