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Abstract
Honokiol is a natural product and an emerging drug for a wide variety of malignancies, including hematopoietic malignancies, sarcomas, and common epithelial tumors. The broad range of activity of honokiol against numerous malignancies with diverse genetic backgrounds suggests that honokiol is inhibiting an activity that is common to multiple malignancies. Oncogenic transcription factor FOXM1 is one of the most overexpressed oncoproteins in human cancer. Here we found that honokiol inhibits FOXM1-mediated transcription and FOXM1 protein expression. More importantly, we found that honokiol’s inhibitory effect on FOXM1 is a result of binding of honokiol to FOXM1. This binding is specific to honokiol, a dimerized allylphenol, and was not observed in compounds that either were monomeric allylphenols or un-substituted dihydroxy phenols. This indicates that both substitution and dimerization of allylphenols are required for physical interaction with FOXM1. We thus demonstrate a novel and specific mechanism for FOXM1 inhibition by honokiol, which partially may explain its anticancer activity in cancer cells.
Highlights
Forkhead family member Forkhead Box M1 (FOXM1) is ubiquitously expressed in a wide range of human cancers and it contributes to several different aspects of oncogenesis[1]
We found that proteasome inhibitors target FOXM13 and recently we determined the mechanism for the suppression of FOXM1: proteasome inhibitors stabilize HSP70, which binds to FOXM1 and inhibits the activity of FOXM1 as a transcription factor[4]
We demonstrated that after binding to FOXM1, HSP70 inhibits the DNAbinding of FOXM1 and its transcriptional activity
Summary
Forkhead family member Forkhead Box M1 (FOXM1) is ubiquitously expressed in a wide range of human cancers and it contributes to several different aspects of oncogenesis[1]. Stephanou mediated inhibition of FOXM1 transcriptional activity leads to the suppression of its protein expression[4,5]. To evaluate the effects of honokiol on FOXM1 transcriptional activity, we utilized the U2OS-derived C3-luc cell line[18] with stable expression of the doxycyclineinducible FOXM1-GFP fusion protein and the 6× FOXM1b-TATA-luciferase reporter plasmid.
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