FOXM1 targets NBS1 to regulate DNA damage-induced senescence and epirubicin resistance

Abstract

FOXM1 is implicated in genotoxic drug resistance but its mechanism of action remains elusive. We show here that FOXM1-depletion can sensitize breast cancer cells and MEFs into entering epirubicin-induced senescence, with the loss of long-term cell proliferation ability, the accumulation of γH2AX foci, and the induction of senescence-associated β-galactosidase activity and cell morphology. Conversely, reconstitution of FOXM1 in FOXM1-deficient MEFs alleviates the accumulation of senescence-associated γH2AX foci. We also demonstrate that FOXM1 regulates NBS1 at the transcriptional level through an FHRE on its promoter. Like FOXM1, NBS1 is overexpressed in the epirubicin-resistant MCF-7EpiR cells and its expression level is low but inducible by epirubicin in MCF-7 cells. Consistently, overexpression of FOXM1 augmented and FOXM1 depletion reduced NBS1 expression and epirubicin-induced ATM phosphorylation in breast cancer cells. Together these findings suggest that FOXM1 increases NBS1 expression and ATM phosphorylation, possibly through increasing the levels of the MRN(MRE11/RAD50/NBS1) complex. Consistent with this idea, the loss of P-ATM induction by epirubicin in the NBS1-deficient NBS1-LBI fibroblasts can be rescued by NBS1 reconstitution. Resembling FOXM1, NBS1 depletion also rendered MCF-7 and MCF-7EpiR cells more sensitive to epirubicin-induced cellular senescence. In agreement, the DNA repair-defective and senescence phenotypes in FOXM1-deficent cells can be effectively rescued by overexpression of NBS1. Moreover, overexpression of NBS1 and FOXM1 similarly enhanced and their depletion downregulated HR DNA repair activity. Crucially, overexpression of FOXM1 failed to augment HR activity in the background of NBS1 depletion, demonstrating that NBS1 is indispensable for the HR function of FOXM1. The physiological relevance of the regulation of NBS1 expression by FOXM1 is further underscored by the strong and significant correlation between nuclear FOXM1 and total NBS1 expression in breast cancer patient samples, further suggesting that NBS1 as a key FOXM1 target gene involved in DNA damage response, genotoxic drug resistance and DNA damage-induced senescence.

Association between FOXM1 and hedgehog signaling pathway in human cervical carcinoma by tissue microarray analysis

“…FOXM1 is a dynamic cancer-associated biomarker involved in the regulation of various biological processes, including cell cycle progression, differentiation, metastasis, invasion and angiogenesis (14)(15)(16)(17)(18). In a previous study, the present authors demonstrated that FOXM1 was overexpressed in cervical cancer tissues, and its nuclear expression was observed to be correlated with the pathological grade of the tumor (19).…”

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

“…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).…”

“…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).…”

“…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.…”