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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE277341 | GEO | 2025/09/18

REPOSITORIES: GEO

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Project description:Aims: Cardiac fibroblasts (CFs) play a crucial role in cardiac remodelling, which is a common cause of heart failure (HF). However, the molecular mechanisms underlying the fibroblast-to-myofibroblast transition remain largely unknown. Foxm1 is well known in various cardiopulmonary pathologies. However, Foxm1-driven CF activation in the progression of cardiac remodelling to HF remains to be investigated. Methods: Changes in Foxm1 expression were assessed in samples from patients with HF and mice with transverse aortic constriction (TAC)-induced cardiac remodelling. Pharmacologic antagonist FDI-6 was used to explore the effects of Foxm1 inhibition on post-TAC outcomes. Tcf21-Cre and PostnMCM were used to evaluate Foxm1 loss- and gain-of-function in CFs and myofibroblasts, respectively. Cardiac function and remodelling were examined by echocardiography and histological analysis. Foxm1 downstream target genes were identified by mass spectrometry (MS) and transcriptomic analysis. Post-translational regulation was evaluated by in vitro chromatin immunoprecipitation, co-immunoprecipitation, and ubiquitination assays. Pharmacological inhibition of Usp10 or knockout of p38γ in vivo verified the signalling pathway by which Foxm1 regulated cardiac remodelling. Results: Foxm1 was upregulated in human HF samples as well as in the mouse cardiac remodelling model. CFs were the primary cell type responsible for Foxm1 upregulation. Foxm1 pharmacological inhibition or genetic knockout in CFs or myofibroblasts significantly attenuated TAC-induced cardiac remodelling and HF. Conversely, conditional overexpression of Foxm1 in CFs or myofibroblasts resulted in more severe pathological cardiac remodelling and dysfunction. Combined RNA-sequencing and MS analysis revealed that Foxm1 promoted Usp10 expression by binding to its promoter. Usp10 interacted with p38γ, resulting in p38γ deubiquitination and thus inﬂuencing the downstream p38 mitogen-activated protein kinase (MAPK) signalling pathway. Pharmacological inhibition of Usp10 or genetic knockout of p38γ ameliorated the exacerbated TAC-induced cardiac remodelling in mice with myofibroblast-specific Foxm1 overexpression. Conclusion: Our findings reveal an essential role of Foxm1 in CF activation during cardiac remodelling. These results suggest that targeting the Foxm1/Usp10/p38γ MAPK axis may represent a new potential therapeutic strategy against pathological cardiac remodelling and HF.

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

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