FOXM1 repression increases mitotic death upon antimitotic chemotherapy through BMF upregulation

Sara Vaz, Fábio J. Ferreira, Joana C. Macedo, Gil Leor, Uri Ben-David, José Bessa, Elsa Logarinho*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


Inhibition of spindle microtubule (MT) dynamics has been effectively used in cancer treatment. Although the mechanisms by which MT poisons elicit mitotic arrest are fairly understood, efforts are still needed towards elucidating how cancer cells respond to antimitotic drugs owing to cytotoxicity and resistance side effects. Here, we identified the critical G2/M transcription factor Forkhead box M1 (FOXM1) as a molecular determinant of cell response to antimitotics. We found FOXM1 repression to increase death in mitosis (DiM) due to upregulation of the BCL-2 modifying factor (BMF) gene involved in anoikis, an apoptotic process induced upon cell detachment from the extracellular matrix. FOXM1 binds to a BMF intronic cis-regulatory element that interacts with both the BMF and the neighbor gene BUB1B promoter regions, to oppositely regulate their expression. This mechanism ensures that cells treated with antimitotics repress BMF and avoid DiM when FOXM1 levels are high. In addition, we show that this mechanism is partly disrupted in anoikis/antimitotics-resistant tumor cells, with resistance correlating with lower BMF expression but in a FOXM1-independent manner. These findings provide a stratification biomarker for antimitotic chemotherapy response.

Original languageEnglish
Article number542
JournalCell Death and Disease
Issue number6
StatePublished - Jun 2021


FundersFunder number
Horizon 2020 Framework ProgrammeERC-2015-StG-680156-ZPR
European Research Council
Fundação para a Ciência e a TecnologiaPD/BD/105745/2014, CEECIND/03482/2018, PTDC/BIA-CEL/31120/ 2017, SFRH/BD/125017/2016, IF/00916/2014, POCI-01-0145-FEDER-031120, POCI-01-0145-FEDER-007274
European Regional Development Fund
Programa Operacional Temático Factores de Competitividade


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