转录因子FOXM1在细胞周期进展和肿瘤发生中起关键作用，在快速增殖的细胞和各种肿瘤组织中高表达，FOXM1高表达与不良预后相关。然而，FOXM1 失调的机制尚不完全清楚。在这里，我们发现 ABL1（一种非受体酪氨酸激酶）有助于 FOXM1 的高表达和 FOXM1 依赖性肿瘤的发展。从机制上讲，ABL1 直接结合 FOXM1 并介导 FOXM1 在多个酪氨酸 (Y) 残基上的磷酸化。在这些磷酸化 Y 位点中，pY575 对于 FOXM1 的稳定性是不可或缺的，因为该位点的磷酸化可保护 FOXM1 免受泛素蛋白酶体降解。 FOXM1 与 CDH1（E3 泛素连接酶后期促进复合物/环体 (APC/C) 的共激活剂，负责 FOXM1 降解）的相互作用受到 Y575 磷酸化的显着抑制。磷酸缺陷型 FOXM1(Y575F) 突变体表现出泛素化增加、半衰期缩短，因此丰度大幅降低。与野生型细胞相比，通过CRISPR/Cas9产生的表达内源FOXM1（Y575F）的纯合Cr-Y575F细胞系表现出明显延迟的有丝分裂进程，阻碍集落形成并抑制异种移植肿瘤的生长。总体而言，我们的研究表明 ABL1 激酶参与 FOXM1 高表达，为 ABL1 可能作为治疗 FOXM1 高表达肿瘤的治疗靶点提供了明确的证据。© 2024。作者。

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).