FOXM1 repression increases mitotic death upon antimitotic chemotherapy through BMF upregulation.
Cell Death Dis
; 12(6): 542, 2021 05 25.
Article
in En
| MEDLINE
| ID: mdl-34035233
ABSTRACT
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Cell Death
/
Antimitotic Agents
/
Forkhead Box Protein M1
Type of study:
Prognostic_studies
Limits:
Aged80
/
Child
/
Humans
/
Male
Language:
En
Journal:
Cell Death Dis
Year:
2021
Document type:
Article
Affiliation country:
Portugal