Title:Insights into a Critical Role of the FOXO3a-FOXM1 Axis in DNA Damage Response and Genotoxic Drug Resistance
Volume: 17
Issue: 2
Author(s): Gabriela Nestal de Moraes, Laura Bella, Stefania Zona, Matthew J. Burton and Eric W.-F. Lam
Affiliation:
Keywords:
Cancer, DNA damage, drug resistance, FOXM1, FOXO3a, genotoxic agents, transcriptional targets.
Abstract: FOXO3a and FOXM1 are two forkhead transcription factors with antagonistic roles in cancer
and DNA damage response. FOXO3a functions like a typical tumour suppressor, whereas FOXM1
is a potent oncogene aberrantly overexpressed in genotoxic resistant cancers. FOXO3a not only represses
FOXM1 expression but also its transcriptional output. Recent research has provided novel insights
into a central role for FOXO3a and FOXM1 in DNA damage response. The FOXO3a-FOXM1
axis plays a pivotal role in DNA damage repair and the accompanied cellular response through regulating
the expression of genes essential for DNA damage sensing, mediating, signalling and repair as
well as for senescence, cell cycle and cell death control. In this manner, the FOXO3a-FOXM1 axis also holds the key to
cell fate decision in response to genotoxic therapeutic agents and controls the equilibrium between DNA repair and cell
termination by cell death or senescence. As a consequence, inhibition of FOXM1 or reactivation of FOXO3a in cancer
cells could enhance the efficacy of DNA damaging cancer therapies by decreasing the rate of DNA repair and cell survival
while increasing senescence and cell death. Conceptually, targeting FOXO3a and FOXM1 may represent a promising
molecular therapeutic option for improving the efficacy and selectivity of DNA damage agents, particularly in genotoxic
agent resistant cancer. In addition, FOXO3a, FOXM1 and their downstream transcriptional targets may also be reliable
diagnostic biomarkers for predicting outcome, for selecting therapeutic options, and for monitoring treatments in
DNA-damaging agent therapy.
