FOXM1 repression increases mitotic death upon antimitotic chemotherapy through BMF upregulation

Area of Science:

• Molecular Biology
• Cancer Research
• Cell Biology

Background:

• Microtubule (MT) dynamics inhibition is a key cancer treatment strategy.
• Understanding cancer cell responses to antimitotic drugs is crucial due to resistance and cytotoxicity.
• Forkhead box M1 (FOXM1) is a critical transcription factor in the G2/M phase.

Purpose of the Study:

• To identify molecular determinants of cancer cell response to antimitotic drugs.
• To elucidate the role of FOXM1 in mediating cell fate under antimitotic treatment.
• To investigate the mechanism linking FOXM1, BMF, and anoikis in cancer cells.

Main Methods:

• Investigated FOXM1's role in regulating cell death in mitosis (DiM).
• Analyzed BCL-2 modifying factor (BMF) gene expression and its regulation by FOXM1.
• Examined FOXM1's binding to cis-regulatory elements and its interaction with BMF and BUB1B promoters.
• Assessed the mechanism in anoikis/antimitotics-resistant tumor cells.

Main Results:

• FOXM1 repression increases DiM via BMF upregulation.
• FOXM1 directly binds to a BMF intronic element, oppositely regulating BMF and BUB1B expression.
• High FOXM1 levels promote BMF repression and prevent DiM in antimitotic-treated cells.
• Resistance to anoikis/antimitotics involves a disrupted FOXM1-BMF pathway, with lower BMF expression independent of FOXM1.

Conclusions:

• FOXM1 is a key regulator of cancer cell survival during antimitotic therapy.
• The FOXM1-BMF regulatory axis is critical for preventing death in mitosis.
• Disruption of this axis contributes to antimitotic resistance.
• FOXM1 and BMF expression levels may serve as biomarkers for stratifying patient response to antimitotic chemotherapy.