Long non-coding RNA AGAP2-AS1 exerts oncogenic properties in glioblastoma by epigenetically silencing TFPI2 through EZH2 and LSD1.

Wenzheng Luo,Xueyuan Li,Shanshan Zhao,Xuqiang Zhu,Zhenyu Song

doi:10.18632/aging.102018

Wenzheng Luo, Xueyuan Li + Show 3 more

Open Access

https://doi.org/10.18632/aging.102018

Copy DOI

Abstract

Long non-coding RNAs (LncRNAs) have attracted increasing attention for their important regulation functions in a wide range of malignancies. AGAP2-AS1 was demonstrated as an oncogene in several cancers, including glioblastoma (GBM). However, the biological mechanisms of AGAP2-AS1 in GBM progression are still unclear. Herein, we found that AGAP2-AS1 expression was up-regulated in GBM tissues and cells. High AGAP2-AS1 expression may predict a poor prognosis in GBM patients. Functionally, silencing of AGAP2-AS1 suppressed proliferation and invasion, while enhanced apoptosis in GBM cells. Overexpression of AGAP2-AS1 promoted cell proliferation and invasion. Mechanically, AGAP2-AS1 could interact with EZH2 and LSD1, recruiting them to TFPI2 promoter region to inhibit its transcription. Moreover, TFPI2 overexpression decreased proliferation and invasion, and facilitated apoptosis in GBM cells. Furthermore, the tumor-suppressive effects mediated by AGAP2-AS1 knockdown were greatly reversed following down-regulation of TFPI2. Also, suppression of AGAP2-AS1 impaired tumor growth of GBM in vivo. In summary, AGAP2-AS1 exerts oncogenic functions in GBM by epigenetically silencing TFPI2 expression through binding to EZH2 and LSD1, illuminating a novel mechanism of AGAP2-AS1 in GBM development and furnishing a prospective therapeutic method to combat GBM.

Highlights

Glioblastoma (GBM) is the most common malignant primary brain tumor in adults and one of the most deadly types of human cancers [1]
We found that AGAP2-AS1 expression was increased in GBM tissues and cells
It is widely accepted that Long non-coding RNAs (lncRNAs) affect cancer phenotypes by modulating target gene expression via various mechanisms, such as chromatin modification, genomic imprinting, RNA decay and sponging miRNAs [20]

Summary

Introduction

Glioblastoma (GBM) is the most common malignant primary brain tumor in adults and one of the most deadly types of human cancers [1]. In 2016, it is estimated that there are 12,120 newly diagnosed GBM patients in the United States, with a 5-year survival rate of only 5% [2]. In spite of the advancement of surgical intervention, radiation, and systemic chemotherapy, the prognosis for patients with GBM remains dismal, with a median survival of 15 months [3, 4]. LncRNAs are reported to participate in diverse pathological events in human malignancies by modulating mRNA stability, RNA splicing, chromatin structure, and miRNA-mediated gene regulation [5, 6]. Increasing lncRNAs have been identified as oncogenes or tumor suppressors in different cancers, including glioma [7, 8]

Methods

Results

Conclusion