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CKAP4-mediated activation of FOXM1 via phosphorylation pathways regulates malignant behavior of glioblastoma cells
Kaiyue Xu1, Kaiqian Zhang2, Jiying Ma1
1National Engineering Research Center for Miniaturized Detection Systems, College of Life Sciences, Northwest University, Xi'an, Shaanxi, China.
Objective:
CKAP4 (Cytoskeleton Associated Protein 4) has been reported as an important regulator of carcinogenesis. A great deal of uncertainty still surrounds the possible molecular mechanism of CKAP4 involvement in GBM. We aimed to specifically elucidate the putative role of CKAP4 in the development of GBM.
Methods:
We identified divergent proteomics landscapes of GBM and adjacent normal tissues using mass spectrometry-based label-free quantification. Bioinformatics analysis of differentially expressed proteins (DEPs) led to the identification of CKAP4 as a hub gene. Based on the Chinese Glioma Genome Atlas data, we characterized the elevated expression of CKAP4 in GBM and developed a prognostic model. The influence of CKAP4 on malignant behavior of GBM was detected in vitro and vivo, as well as its downstream target and signaling pathways.
Results:
The prognosis model displayed accuracy and reliability for the probability of survival of patients with gliomas. CKAP4 knockdown remarkably reduced the malignant potential of GBM cells, whereas its overexpression reversed these effects in GBM cells and xenograft mice. Moreover, we demonstrated that overexpression of CKAP4 leads to increased FOXM1 (Forkhead Box M1) expression in conjunction with an increased level of AKT and ERK phosphorylation. Inhibition of both pathways had synergistic effects, resulting in greater effectiveness of inhibition. CKAP4 could reverse the deregulation of FOXM1 triggered by inhibition of AKT and ERK signaling.
Conclusions:
This is the first study to reveal a CKAP4-FOXM1 signaling cascade that contributes to the malignant phenotype of GBMs. The CKAP4-based prognostic model would facilitate individualized treatment decisions for glioma patients.
Insights
Cytoskeleton Associated Protein 4 (CKAP4) drives glioblastoma (GBM) malignancy through the FOXM1 pathway. Targeting CKAP4 offers a novel therapeutic strategy and aids in developing prognostic models for glioma patients.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Cytoskeleton Associated Protein 4 (CKAP4) is implicated in carcinogenesis, but its precise role in glioblastoma (GBM) remains unclear.
- Understanding CKAP4's molecular mechanisms in GBM is crucial for developing targeted therapies.
Purpose of the Study:
- To elucidate the specific role of CKAP4 in the development and progression of Glioblastoma Multiforme (GBM).
- To identify CKAP4 as a potential therapeutic target and prognostic biomarker for GBM.
Main Methods:
- Proteomics analysis of GBM versus normal tissues to identify differentially expressed proteins (DEPs).
- Bioinformatics analysis to identify CKAP4 as a hub gene and develop a prognostic model using Chinese Glioma Genome Atlas (CGGA) data.
- In vitro and in vivo experiments to assess CKAP4's influence on GBM cell behavior and downstream signaling pathways (FOXM1, AKT, ERK).
Main Results:
- CKAP4 expression is elevated in GBM, and a CKAP4-based prognostic model accurately predicts patient survival.
- CKAP4 knockdown suppressed GBM malignancy, while overexpression promoted it in cells and xenograft models.
- CKAP4 overexpression upregulated FOXM1, AKT, and ERK phosphorylation; inhibiting these pathways synergistically reduced GBM's malignant potential.
Conclusions:
- This study reveals a novel CKAP4-FOXM1 signaling cascade crucial for GBM's malignant phenotype.
- The developed CKAP4-based prognostic model can assist in personalized treatment strategies for glioma patients.
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