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ARID4B Knockdown Suppresses PI3K/AKT Signaling and Induces Apoptosis in Human Glioma Cells

Authors Luo SM, Tsai WC, Tsai CK, Chen Y, Hueng DY

Received 14 October 2020

Accepted for publication 9 December 2020

Published 10 March 2021 Volume 2021:14 Pages 1843—1855

DOI https://doi.org/10.2147/OTT.S286837

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Dr William Cho


Siou-Min Luo,1 Wen-Chiuan Tsai,2 Chia-Kuang Tsai,1,3 Ying Chen,4 Dueng-Yuan Hueng1,5,6

1Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan, Republic of China; 2Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China; 3Department of Neurology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China; 4Department of Biology and Anatomy, National Defense Medical Center, Taipei, Taiwan, Republic of China; 5Department of Neurological Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China; 6Department of Biochemistry, National Defense Medical Center, Taipei, Taiwan, Republic of China

Correspondence: Dueng-Yuan Hueng No. 325, Sec. 2, Chenggong Road, Neihu Dist., Taipei City, 114, Taiwan, Republic of China
Tel +886-2-8792-7177
Email [email protected]

Purpose: Glioblastoma multiforme is a highly malignant primary brain cancer with a poor prognosis. We recently reported that ARID4B could potentially serve as a biomarker associated with poor survival in glioma patients. However, the function of ARID4B in human gliomas remains unclear. The aim of this study is to investigate the molecular cell biology role of ARID4B in human glioma cells.
Materials and Methods: Gene Expression Omnibus (GEO) and Human Protein Atlas (HPA) datasets were analyzed for the expression of ARID4B in WHO pathological grading, overall survival and immunohistochemical staining. Using quantitative RT-PCR and Western blotting, those findings were confirmed in normal brain tissue and glioma cell lines. ARID4B knockdown was conducted via lentivirus-based transfection of small hairpin RNA in human glioma cells to investigate cell proliferation, cell cycle, and apoptosis.
Results: In the present study, our analysis of GEO datasets showed that ARID4B mRNA expression is higher in WHO grade IV tumors (n = 81) than in non-tumor control tissue (n = 23, P < 0.0001). ARID4B knockdown suppressed glioma cell proliferation and induced G1 phase arrest via the PI3K/AKT pathway. It also increased expression of HDAC1, leading to higher acetyl-p53 and acetyl-H3 levels and reduced glioma cell migration and invasion. These effects were mediated via downregulation of AKT pathway components, including p-mTOR, p-PI3K and p-AKT. ARID4B knockdown also led to downregulation of Cyclin D1, which increased apoptosis in human glioma cells.
Conclusion: These findings that ARID4B expression correlates positively with WHO pathologic grading in glioma. ARID4B knockdown suppresses PI3K/AKT signaling and induces apoptosis in human glioma cells. These results suggests that ARID4B acts as an oncogene in human gliomas.

Keywords: invasion, migration, cell proliferation, mTOR, Cyclin D1

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