EGFR/EGFRvIII remodels the cytoskeleton via epigenetic silencing of AJAP1 in glioma cells

Chao Yang; Yan-Sheng Li; Qi-Xue Wang; Kai Huang; Jian-Wei Wei; Yun-Fei Wang; Jun-Hu Zhou; Kai-Kai Yi; Kai-Liang Zhang; Bing-Cong Zhou; Cong Liu; Liang Zeng; Chun-Sheng Kang

doi:10.1016/j.canlet.2017.06.007

EGFR/EGFRvIII remodels the cytoskeleton via epigenetic silencing of AJAP1 in glioma cells

Cancer Lett. 2017 Sep 10:403:119-127. doi: 10.1016/j.canlet.2017.06.007. Epub 2017 Jun 17.

Authors

Affiliations

¹ Department of Neurosurgery, Tianjin Medical University General Hospital, Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin 300052, China.
² Department of Neurosurgery, Qilu Hospital of Shandong University, Brain Science Research Institute, Shandong University, China.
³ Department of Neurosurgery, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, PR China.
⁴ Department of Neurosurgery, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, PR China. Electronic address: Liangzeng209@yahoo.com.
⁵ Department of Neurosurgery, Tianjin Medical University General Hospital, Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin 300052, China. Electronic address: kang97061@tmu.edu.cn.

PMID: 28634045
DOI: 10.1016/j.canlet.2017.06.007

Abstract

EGFR amplification and mutations are the most common oncogenic events in GBM. EGFR overexpression correlates with GBM invasion, but the underlying mechanisms are poorly understood. In a previous study, we showed that AJAP1 is involved in regulating F-actin to inhibit the invasive ability of GBM. In addition, in a GBM cell line, the AJAP1 promoter was highly bound by H3K27me3 and, through bioinformatics analysis, we found that AJAP1 expression was negatively correlated with EGFR. In this study, we found that the pathway downstream of EGFR had a higher activation level in GBM cell lines, which led to excessive tumor suppressor silencing. Therefore, we deduced that in glioma cells, the pathway downstream of EGFR remodels the cytoskeleton via AJAP1 epigenetic silencing to enhance invasion. Furthermore, MK2206 reversed AJAP1 downregulation by inhibiting the EGFR pathway. In vivo, MK2206 also inhibited the proliferation and local invasion of 87-EGFRvIII. These data suggest that activation of the EGFR signal transduction pathway genetically silences anti-oncogenes to enhance GBM malignancy. MK2206 might be a promising therapeutic for EGFR/EGFRvIII-positive GBMs.

Keywords: AJAP1; Cytoskeleton; EGFR pathway; Glioblastoma; MK2206.

MeSH terms

Actin Cytoskeleton / metabolism*
Animals
Antineoplastic Agents / pharmacology
Brain Neoplasms / drug therapy
Brain Neoplasms / genetics
Brain Neoplasms / metabolism*
Cell Adhesion Molecules / genetics
Cell Adhesion Molecules / metabolism*
Cell Line, Tumor
Cell Movement* / drug effects
Cell Proliferation / drug effects
Computational Biology
DNA Methylation*
Databases, Genetic
Enhancer of Zeste Homolog 2 Protein / metabolism
Epigenesis, Genetic*
ErbB Receptors / genetics
ErbB Receptors / metabolism*
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Heterocyclic Compounds, 3-Ring / pharmacology
Humans
Mice, Inbred BALB C
Mice, Nude
Neoplasm Invasiveness
Phosphatidylinositol 3-Kinase / metabolism
Promoter Regions, Genetic
Protein Kinase Inhibitors / pharmacology
Proto-Oncogene Proteins c-akt / antagonists & inhibitors
Proto-Oncogene Proteins c-akt / metabolism
RNA Interference
Signal Transduction
Transfection
Xenograft Model Antitumor Assays

Substances

AJAP1 protein, human
Antineoplastic Agents
Cell Adhesion Molecules
Heterocyclic Compounds, 3-Ring
MK 2206
Protein Kinase Inhibitors
epidermal growth factor receptor VIII
EZH2 protein, human
Enhancer of Zeste Homolog 2 Protein
Phosphatidylinositol 3-Kinase
EGFR protein, human
ErbB Receptors
Proto-Oncogene Proteins c-akt