Suppressing A549 lung cancer cells by targeting FOXM1 with a 71-residue self-derived region.

High FOXM1 expression levels have been associated with poor prognosis in patients across various cancer types. FOXM1 plays a multifunctional role in tumorigenesis, including proliferation, anti-apoptosis, and metastasis, making it a potential marker and attractive therapeutic target. We screened FOXM1 truncations and identified a 71-residue region (51-121) from N-terminal repression domain (NRD) that effectively targets FOXM1 transcriptional activity in luciferase reporter assays. Specifically, FOXM1 transcriptional activation domain (TAD) interacted with NRD 51-121 in immunoprecipitation assays. Further analysis showed that mutations hindering hydrophobicity or mimicking PLK1 phosphorylation within TAD blocked the association between NRD 51-121 and TAD. Additionally, expressing NRD 51-121 in A549 cells resulted in reduced proliferation, increased apoptosis, and enhanced senescence compared to controls. RNA sequencing indicated that FOXM1 is a key factor influencing gene expression profiles in A549 cells expressing NRD 51-121. Collectively, our study suggests a potential cancer therapy targeting FOXM1. This approach suppresses FOXM1 by expression of NRD 51-121, which supposedly binds to TAD, thereby inactivating its transcriptional networks and limiting cancer growth.