FoxM1 insufficiency hyperactivates Ect2–RhoA–mDia1 signaling to drive cancer

Jazeel F. Limzerwala, Karthik B. Jeganathan, Jake A. Kloeber, Brian A. Davies, Cheng Zhang, Ines Sturmlechner, Jian Zhong, Raul Fierro Velasco, Alan P. Fields, Yaxia Yuan, Darren J. Baker, Daohong Zhou, Hu Li, David J. Katzmann, Jan M. van Deursen

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)1010-1024
Number of pages15
JournalNature Cancer
Volume1
Issue number10
DOIs
StatePublished - Oct 1 2020

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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