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

Title: The Forkhead Box M1 protein regulates BRIP1 expression and DNA damage repair in epirubicin treatment
Authors: Monteiro, LJ
Khongkow, P
Kongsema, M
Morris, JR
Man, C
Weekes, D
Koo, C-Y
Gomes, AR
Pinto, PH
Varghese, V
Kenny, LM
Coombes, RC
Freire, R
Medema, RH
Lam, EW-F
Item Type: Journal Article
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 (DSBs), 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 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 harbouring an integrated direct repeat green fluorescent protein 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 small interfering RNA downregulates 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.
Issue Date: 29-Oct-2012
Date of Acceptance: 7-Sep-2012
URI: http://hdl.handle.net/10044/1/39230
DOI: http://dx.doi.org/10.1038/onc.2012.491
ISSN: 1476-5594
Publisher: Nature Publishing Group
Start Page: 4634
End Page: 4645
Journal / Book Title: Oncogene
Volume: 32
Issue: 39
Copyright Statement: © 2013 Macmillan Publishers Limited. All rights reserved.
Sponsor/Funder: National Institute for Health Research
Funder's Grant Number: NIHR/CS/009/009
Keywords: Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Oncology
Cell Biology
Genetics & Heredity
BIOCHEMISTRY & MOLECULAR BIOLOGY
CELL BIOLOGY
GENETICS & HEREDITY
ONCOLOGY
FOXM1
BRIP1
DNA damage
epirubicin
resistance
breast cancer
BREAST-CANCER CELLS
TRANSCRIPTION FACTOR FOXM1
DOUBLE-STRAND BREAKS
HOMOLOGOUS RECOMBINATION
MAMMALIAN-CELLS
BINDING DOMAIN
RESISTANCE
BACH1
PROGRESSION
GENE
Animals
Antibiotics, Antineoplastic
DNA Breaks, Double-Stranded
DNA Damage
DNA, Neoplasm
DNA-Binding Proteins
Drug Resistance, Neoplasm
Epirubicin
Female
Fibroblasts
Forkhead Transcription Factors
Gamma Rays
Histones
Humans
MCF-7 Cells
Mice
Neoplasm Proteins
RNA Helicases
RNA Interference
RNA, Messenger
RNA, Neoplasm
RNA, Small Interfering
Radiation Tolerance
Recombinant Fusion Proteins
Recombinational DNA Repair
Fibroblasts
Animals
Humans
Mice
DNA Damage
Epirubicin
RNA Helicases
DNA-Binding Proteins
Neoplasm Proteins
Histones
Recombinant Fusion Proteins
RNA, Small Interfering
DNA, Neoplasm
RNA, Messenger
RNA, Neoplasm
Antibiotics, Antineoplastic
RNA Interference
Drug Resistance, Neoplasm
Gamma Rays
Radiation Tolerance
Female
Forkhead Transcription Factors
DNA Breaks, Double-Stranded
Recombinational DNA Repair
MCF-7 Cells
Oncology & Carcinogenesis
1112 Oncology And Carcinogenesis
1103 Clinical Sciences
Publication Status: Published
Appears in Collections:Division of Surgery
Division of Cancer
Faculty of Medicine



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