Insights into a Critical Role of the FOXO3a-FOXM1 Axis in DNA Damage Response and Genotoxic Drug Resistance

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.

FOXO3a and Posttranslational Modifications Mediate Glucocorticoid Sensitivity in B-ALL

“…It is well-established that Akt (PKB)-mediated phosphorylation and inactivation of FOXO3a culminate in cytoplasmic localization and cell proliferation (2,3). Herein, we showed that in the sensitive B-ALL cell lines, RS4,11 and SUP-B15, FOXO3a became dephosphorylated on Akt-targeted sites, Ser253, Thr315, and Thr32 upon dexamethasone treatment, but its phosphorylation was unaffected by dexamethasone in the resistant REH cells.…”

“…FOXO3a plays an important role in proliferation, apoptosis, autophagy, metabolism, inflammation, differentiation, and stress resistance (3,4). The stability, subcellular localization, the DNA-binding affinity, and the transcriptional activity of FOXO3a are primarily regulated by a complex array of posttranslational modifications (5).…”

Aberrant DNA Double-strand Break Repair Threads in Breast Carcinoma: Orchestrating Genomic Insult Survival

“…Recently, two Forkhead transcription factors forkhead box O3 (FOXO3a) and FOXM1 have been described for their explicit contribution in the DNA damage response. Therefore, ways to explore inhibitors against these two transcription factors are being attempted to augment senescence and cell death in carcinoma 58. Cell cycle checkpoints are potential cellular targets in several carcinomas including the DNA damage response and survival strategies in breast cancer.…”

Multiplicity of acquired cross-resistance in paclitaxel-resistant cancer cells is associated with feedback control of TUBB3 via FOXO3a-mediated ABCB1 regulation

“…Meanwhile, FOXO3a , aside from affecting PTX actions, regulates the DNA damage response and stimulates the DNA repair pathway, which regulates the sensitivity to drugs that target the DNA repair system such as 5-FU and CIS, among others [15, 16]. Forkhead box M1 ( FOXM1 ) and FOXO3a have been observed to compete in binding to similar DNA sequences, which often results in antagonized transcriptional output that has recently been related to genotoxic drug resistance and the response of various cancers to chemotherapy [17, 18]. …”