ABL1-mediated phosphorylation promotes FOXM1-related tumorigenicity by Increasing FOXM1 stability.

Cell death and differentiation 2024 Oct

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The transcription factor FOXM1, which plays critical roles in cell cycle progression and tumorigenesis, is highly expressed in rapidly proliferating cells and various tumor tissues, and high FOXM1 expression is related to a poor prognosis. However, the mechanism responsible for FOXM1 dysregulation is not fully understood. Here, we show that ABL1, a nonreceptor tyrosine kinase, contributes to the high expression of FOXM1 and FOXM1-dependent tumor development. Mechanistically, ABL1 directly binds FOXM1 and mediates FOXM1 phosphorylation at multiple tyrosine (Y) residues. Among these phospho-Y sites, pY575 is indispensable for FOXM1 stability as phosphorylation at this site protects FOXM1 from ubiquitin-proteasomal degradation. The interaction of FOXM1 with CDH1, a coactivator of the E3 ubiquitin ligase anaphase-promoting complex/cyclosome (APC/C), which is responsible for FOXM1 degradation, is significantly inhibited by Y575 phosphorylation. The phospho-deficient FOXM1(Y575F) mutant exhibited increased ubiquitination, a shortened half-life, and consequently a substantially decreased abundance. Compared to wild-type cells, a homozygous Cr-Y575F cell line expressing endogenous FOXM1(Y575F) that was generated by CRISPR/Cas9 showed obviously delayed mitosis progression, impeded colony formation and inhibited xenotransplanted tumor growth. Overall, our study demonstrates that ABL1 kinase is involved in high FOXM1 expression, providing clear evidence that ABL1 may act as a therapeutic target for the treatment of tumors with high FOXM1 expression. © 2024. The Author(s).

Citation

Qincai Dong, Di Wang, Caiwei Song, Chunxue Gong, Yue Liu, Xinwei Zhou, Junjie Yue, Yong Hu, Hainan Liu, Lin Zhu, Xiayang Niu, Tong Zheng, Xun Zhang, Jing Jin, Tingting Wang, Ruixia Ju, Chen Wang, Qian Jiang, Ting Gao, Yanwen Jin, Ping Li, Yan Wang, Chunmei Zhang, Guang-Fei Wang, Cheng Cao, Xuan Liu. ABL1-mediated phosphorylation promotes FOXM1-related tumorigenicity by Increasing FOXM1 stability. Cell death and differentiation. 2024 Oct;31(10):1285-1301