FOXM1 is critical for the fitness recovery of chromosomally unstable cells

• Verfasst von: Pan, Fan [VerfasserIn]
• Verfasst von: Chocarro, Sara [VerfasserIn]
• Verfasst von: Ramos, Maria [VerfasserIn]
• Verfasst von: Chen, Yuanyuan [VerfasserIn]
• Verfasst von: Alonso de la Vega, Alicia [VerfasserIn]
• Verfasst von: Somogyi, Kalman [VerfasserIn]
• Verfasst von: Sotillo, Rocio [VerfasserIn]
• Titel: FOXM1 is critical for the fitness recovery of chromosomally unstable cells
• Verf.angabe: Fan Pan, Sara Chocarro, Maria Ramos, Yuanyuan Chen, Alicia Alonso de la Vega, Kalman Somogyi and Rocio Sotillo
• Jahr: 2023
• Umfang: 17 S.
• Fussnoten: Veröffentlicht: 14. Juli 2023 ; Gesehen am 18.08.2023
• Titel Quelle: Enthalten in: Cell death & disease
• Ort Quelle: London [u.a.] : Nature Publishing Group, 2010
• Jahr Quelle: 2023
• Band/Heft Quelle: 14(2023), 7, Seite 1-17
• ISSN Quelle: 2041-4889
• DOI: doi:10.1038/s41419-023-05946-2
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Cancer
• Sach-SW: Cell biology
• K10plus-PPN: 1856530310

Abstract

Tumor progression and evolution are frequently associated with chromosomal instability (CIN). Tumor cells often express high levels of the mitotic checkpoint protein MAD2, leading to mitotic arrest and cell death. However, some tumor cells are capable of exiting mitosis and consequently increasing CIN. How cells escape the mitotic arrest induced by MAD2 and proliferate with CIN is not well understood. Here, we explored loss-of-function screens and drug sensitivity tests associated with MAD2 levels in aneuploid cells and identified that aneuploid cells with high MAD2 levels are more sensitive to FOXM1 depletion. Inhibition of FOXM1 promotes MAD2-mediated mitotic arrest and exacerbates CIN. Conversely, elevating FOXM1 expression in MAD2-overexpressing human cell lines reverts prolonged mitosis and rescues mitotic errors, cell death and proliferative disadvantages. Mechanistically, we found that FOXM1 facilitates mitotic exit by inhibiting the spindle assembly checkpoint (SAC) and the expression of Cyclin B. Notably, we observed that FOXM1 is upregulated upon aneuploid induction in cells with dysfunctional SAC and error-prone mitosis, and these cells are sensitive to FOXM1 knockdown, indicating a novel vulnerability of aneuploid cells.