CDI Exerts Anti-Tumor Effects by Blocking the FoxM1-DNA Interaction

The Forkhead box protein M1 (FoxM1) is an appealing target for anti-cancer therapeutics as this cell proliferation-associated transcription factor is overexpressed in most human cancers. FoxM1 is involved in tumor invasion, angiogenesis, and metastasis. To discover novel inhibitors that disrupt the...

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Bibliographic Details
Published in:Biomedicines 2022-07, Vol.10 (7), p.1671
Main Authors: Jang, Woo Dae, Lee, Mi Young, Mun, Jihye, Lim, Gyutae, Oh, Kwang-Seok
Format: Article
Language:English
Subjects:
Angiogenesis
anti-tumor activity
Antibodies
Apoptosis
Breast cancer
Cdc25B phosphatase
CDI
Cell cycle
Cell growth
Cell proliferation
Deoxyribonucleic acid
DNA
Forkhead protein
FoxM1
FoxM1-DNA interaction
Gene expression
Glycerol
Kinases
Metastases
molecular modeling
Oligonucleotides
Proteins
RNA-Seq
Tumors
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Summary:The Forkhead box protein M1 (FoxM1) is an appealing target for anti-cancer therapeutics as this cell proliferation-associated transcription factor is overexpressed in most human cancers. FoxM1 is involved in tumor invasion, angiogenesis, and metastasis. To discover novel inhibitors that disrupt the FoxM1-DNA interaction, we identified CDI, a small molecule that inhibits the FoxM1–DNA interaction. CDI was identified through an assay based on the time-resolved fluorescence energy transfer response of a labeled consensus oligonucleotide that was bound to a recombinant FoxM1-dsDNA binding domain (FoxM1-DBD) protein and exhibited potent inhibitory activity against FoxM1-DNA interaction. CDI suppressed cell proliferation and induced apoptosis in MDA-MB-231 cells obtained from a breast cancer patient. Furthermore, it decreased not only the mRNA and protein expression of FoxM1 but also that of downstream targets such as CDC25b. Additionally, global transcript profiling of MDA-MB-231 cells by RNA-Seq showed that CDI decreases the expression of FoxM1-regulated genes. The docking and MD simulation results indicated that CDI likely binds to the DNA interaction site of FoxM1-DBD and inhibits the function of FoxM1-DBD. These results of CDI being a possible effective inhibitor of FoxM1-DNA interaction will encourage its usage in pharmaceutical applications.
ISSN:2227-9059
2227-9059
DOI:10.3390/biomedicines10071671