FoxM1 activates genes that regulate S–G2–M cell-cycle progression and, when overexpressed, is associated with poor clinical outcome in multiple cancers. Here we identify FoxM1 as a tumor suppressor in mice that, through its N-terminal domain, binds to and inhibits Ect2 to limit the activity of RhoA GTPase and its effector mDia1, a catalyst of cortical actin nucleation. FoxM1 insufficiency impedes centrosome movement through excessive cortical actin polymerization, thereby causing the formation of nonperpendicular mitotic spindles that missegregate chromosomes and drive tumorigenesis in mice. Importantly, low FOXM1 expression correlates with RhoA GTPase hyperactivity in multiple human cancer types, indicating that suppression of the newly discovered Ect2–RhoA–mDia1 oncogenic axis by FoxM1 is clinically relevant. Furthermore, by dissecting the domain requirements through which FoxM1 inhibits Ect2 guanine nucleotide-exchange factor activity, we provide mechanistic insight for the development of pharmacological approaches that target protumorigenic RhoA activity.

FoxM1 激活调节 S–G2–M 细胞周期进程的基因，当过度表达时，与多种癌症的不良临床结果相关。在这里，我们将 FoxM1 确定为小鼠肿瘤抑制因子，通过其 N 末端结构域结合并抑制 Ect2，以限制 RhoA GTPase 及其效应子 mDia1（皮质肌动蛋白成核催化剂）的活性。 FoxM1不足会通过过度的皮质肌动蛋白聚合阻碍中心体运动，从而导致非垂直的有丝分裂纺锤体的形成，从而使染色体错误分离并驱动小鼠肿瘤发生。重要的是， FOXM1低表达与多种人类癌症类型中的 RhoA GTPase 过度活跃相关，表明 FoxM1 对新发现的 Ect2-RhoA-mDia1 致癌轴的抑制具有临床相关性。此外，通过剖析 FoxM1 抑制 Ect2 鸟嘌呤核苷酸交换因子活性的结构域要求，我们为开发针对促肿瘤 RhoA 活性的药理学方法提供了机制见解。