The Forkhead Box M1 protein regulates BRIP1 expression and DNA damage repair in epirubicin treatment

Abstract

FOXM1 is implicated in genotoxic drug resistance but its role and mechanism of action remain unclear. Here, we establish that γH2AX foci, indicative of DNA double strand breaks, accumulate in a time-dependent manner in the drug sensitive MCF-7 cells but not in the resistant counterparts in response to epirubicin. We find that FOXM1 expression is associated with epirubicin sensitivity and double strand break (DSB) repair. Ectopic expression of FOXM1 can increase cell viability and abrogate DSBs sustained by MCF-7 cells following epirubicin, owing to an enhancement in repair efficiency. Conversely, alkaline comet and γH2AX foci formation assays show that Foxm1-null cells are hypersensitive to DNA damage, epirubicin and γ-irradiation. Furthermore, we find that FOXM1 is required for DNA repair by homologous recombination (HR) but not non-homologous end joining (NHEJ), using HeLa cell lines habouring an integrated direct repeat green fluorescent protein (DR-GFP) reporter for DSB repair. We also identify BRIP1 as a direct transcription target of FOXM1 by promoter analysis and chromatin-immunoprecipitation assay. In agreement, depletion of FOXM1 expression by siRNA down-regulates BRIP1 expression at the protein and mRNA levels in MCF-7 and the epirubicin resistant MCF-7 EpiR cells. Remarkably, the requirement for FOXM1 for DSB repair can be circumvented by reintroduction of BRIP1, suggesting that BRIP1 is an important target of FOXM1 in DSB repair. Indeed, like FOXM1, BRIP1 is needed for HR. These data suggest that FOXM1 regulates BRIP1 expression to modulate epirubicin-induced DNA damage repair and drug resistance.

Depletion of FOXM1 via MET Targeting Underlies Establishment of a DNA Damage–Induced Senescence Program in Gastric Cancer

“…It has become evident that FOXM1 plays a fundamental role in DNA DSBs repair through upregulation of key DDR proteins such as RAD51, NBS1, and BRIP1 (28,30). Likewise, various studies described a role for FOXM1 in the regulation of the senescence program, mainly through its downstream target BMI-1 (41).…”

“…In recent years, many studies have focused on the importance of FOXM1 in both DDR and negative senescence regulation (28)(29)(30). It has become evident that FOXM1 plays a fundamental role in DNA DSBs repair through upregulation of key DDR proteins such as RAD51, NBS1, and BRIP1 (28,30).…”

“…Elevated expression of FOXM1 has been detected in a broad range of malignancies, including gastric cancers, and has been shown to correlate with tumor progression and poor prognosis (27). In recent years, numerous studies have reported FOXM1 playing a crucial role in both homologous recombination repair of DNA DSBs (28,29) and negative regulation of the senescence program (29,30), significantly turning research interests toward FOXM1 as a potential target in cancer therapy.…”

Role of MTDH, FOXM1 and microRNAs in Drug Resistance in Hepatocellular Carcinoma

“…HCC in both wild-type mice or in Arf(−/−)Rosa26-FOXM1 Tg mice was induced by diethylnitrosamine/phenobarbital. These HCC-bearing mice were then injected daily with the cell-penetrating ARF (26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44) peptide inhibitor to pharmacologically reduce FOXM1 activity. After 4 weeks of this treatment, HCC regions displayed reduced tumor cell proliferation and angiogenesis within the HCC region but not in the adjacent normal liver tissue.…”

SUMOylation: A link to future therapeutics

“…This is achieved by controlling transcription of a family of genes involved in DNA double strand damage sensing and recombining homologous repair genes. The role of FOXM1 has also been elucidated in action of taxanes (Monteiro et al, 2012;Zhang et al, 2012;Park et al, 2012). The efficacy of these genotoxic and cytotoxic drugs depends on their ability to resolve the DNA damage response and the control of cell cycle from G2 to M phase (Chien et al, 2008;Alvarez-Fernandez et al, 2010).…”