Sustainable Development Goals

Abstract/Objectives

FOXM1 is a crucial transcription factor that regulates the cell cycle and is closely linked to the progression of various cancers. It not only serves as a potential prognostic biomarker for cancer patients but also represents a promising therapeutic target. This study explores the regulatory mechanisms behind FOXM1's transcriptional activity and its effect on cancer cell growth. For the first time, we demonstrate that FOXM1 functions as a homodimer, with its transcriptional activity and downstream gene expression influenced by conformational changes in both structured regions and intrinsically disordered regions (IDRs) of the protein. Additionally, this research developed a functional peptide that effectively inhibits FOXM1 activity and significantly reduces lung cancer cell growth in both cell culture and the mouse xenograft model, providing an innovative strategy for cancer therapy.

Results/Contributions

The expression level of the transcription factor FOXM1 is significantly elevated in cancer cells, with abnormally increased activity, and is considered a major driver of progression in various cancers. Clinical studies have shown that FOXM1 can serve not only as a biomarker for cancer prognosis but also as a highly promising target for precision therapy.

This study is the first to discover that FOXM1 protein exists in vivo as a homodimer, and that its dimeric conformation changes along with cell cycle progression. In the G1 phase, FOXM1 forms a self-inhibited dimeric configuration through interactions between the C-terminal αβα domain and the N-terminal ββαβ domain. As the cell progresses into the S phase, the kinase PLK1 phosphorylates FOXM1 at residues S715 and S724, triggering a conformational change. At this point, the C-terminal αβα domain interacts with an intrinsically disordered region (IDR), transforming FOXM1 into a self-activated dimeric form, thereby enhancing its transcriptional activity and regulating the expression of cell division-related genes.

Based on this discovery, we identified a key short peptide sequence that modulates FOXM1’s conformational switch. By expressing this peptide, we successfully interfered with FOXM1 activity, significantly inhibiting the proliferation of cultured lung adenocarcinoma cells, and demonstrated potent anti-tumor effects in a mouse tumor model. This study proves that precise inhibition of FOXM1 activity may offer a novel strategy for cancer treatment.

The research included both molecular mechanism studies and mouse tumor model experiments and spanned nearly eight years, during which nearly 200 DNA plasmids were constructed for various tests. Related findings from this study were presented as a poster at the 2023 American Association for Cancer Research (AACR) Annual Meeting, and the full study was published in December 2024 in the top-tier international journal Nucleic Acids Research (impact factor 16.7).


Keywords

Transcription factor, Lung cancer, FOXM1, IDR, PLK1, dimerization, Transcriptional activity, Conformation switch

References

1. https://doi.org/10.1093/nar/gkae988

《Nucleic Acids Research》

Contact Information

王翊青(I-Ching Wang)
icwang@life.nthu.edu.tw