1. Academic Validation
  2. CKAP4-mediated activation of FOXM1 via phosphorylation pathways regulates malignant behavior of glioblastoma cells

CKAP4-mediated activation of FOXM1 via phosphorylation pathways regulates malignant behavior of glioblastoma cells

  • Transl Oncol. 2023 Jan 24;29:101628. doi: 10.1016/j.tranon.2023.101628.
Kaiyue Xu 1 Kaiqian Zhang 2 Jiying Ma 1 Qianqian Yang 1 Ge Yang 1 Tingting Zong 1 Guowei Wang 3 Bo Yan 1 Jule Shengxia 1 Chao Chen 1 Liang Wang 4 Huijuan Wang 5
Affiliations

Affiliations

  • 1 National Engineering Research Center for Miniaturized Detection Systems, College of Life Sciences, Northwest University, Xi'an, Shaanxi, China.
  • 2 National Engineering Research Center for Miniaturized Detection Systems, College of Life Sciences, Northwest University, Xi'an, Shaanxi, China; Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Northwest University, Xi'an, Shaanxi, China.
  • 3 National Engineering Research Center for Miniaturized Detection Systems, College of Life Sciences, Northwest University, Xi'an, Shaanxi, China; Provincial Key Laboratory of Biotechnology of Shaanxi Province, Northwest University, Xi'an, Shaanxi, China.
  • 4 Department of Neurosurgery, Tangdu Hospital of Fourth Military Medical University, 569 Xinsi Road, Xi'an, Shaanxi, China. Electronic address: drwangliang@126.com.
  • 5 National Engineering Research Center for Miniaturized Detection Systems, College of Life Sciences, Northwest University, Xi'an, Shaanxi, China. Electronic address: whj@nwu.edu.cn.
Abstract

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.

Keywords

CKAP4; FOXM1; Glioblastoma; Phosphorylation; Proteomics.

Figures
Products