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FOXM1 repression increases mitotic death upon antimitotic chemotherapy through BMF upregulation

Sara Vaz1,2,3, Fábio J Ferreira1,2,4,5, Joana C Macedo1,2

  • 1i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135, Porto, Portugal.

Cell Death & Disease
|May 26, 2021
PubMed

Insights

Forkhead box M1 (FOXM1) regulates cancer cell response to antimitotic drugs by controlling BCL-2 modifying factor (BMF) expression. This mechanism helps prevent cell death during mitosis, but resistance can occur when it

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.

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