FoxM1 insufficiency hyperactivates Ect2-RhoA-mDia1 signaling to drive cancer.
Nat Cancer
; 1(10): 1010-1024, 2020 10.
Article
in En
| MEDLINE
| ID: mdl-34841254
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 non-perpendicular 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-RhoAmDia1 oncogenic axis by FoxM1 is clinically relevant. Furthermore, by dissecting the domain requirements through which FoxM1 inhibits Ect2 GEF activity, we provide mechanistic insight for the development of pharmacological approaches that target protumorigenic RhoA activity.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Actins
/
Forkhead Box Protein M1
/
Neoplasms
Limits:
Animals
Language:
En
Journal:
Nat Cancer
Year:
2020
Document type:
Article