FoxM1 insufficiency hyperactivates Ect2–RhoA–mDia1 signaling to drive cancer
- 12 October 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Cancer
- Vol. 1 (10), 1010-1024
- https://doi.org/10.1038/s43018-020-00116-1
Abstract
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.Keywords
Funding Information
- Mayo Clinic Graduate School of Biomedical Sciences
- U.S. Department of Health & Human Services | National Institutes of Health (T32 GM65841)
- U.S. Department of Health & Human Services | NIH | National Cancer Institute (R01 CA096985, R01 CA126828, R01 CA168709)
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