Silencing of microRNA-708 promotes cell growth and epithelial-to-mesenchymal transition by activating the SPHK2/AKT/β-catenin pathway in glioma

Yan Chen; Xubin Deng; Weiquan Chen; Pengwei Shi; Mei Lian; Hongxiao Wang; Kewan Wang; Dadi Qian; Dong Xiao; Hao Long

doi:10.1038/s41419-019-1671-5

Silencing of microRNA-708 promotes cell growth and epithelial-to-mesenchymal transition by activating the SPHK2/AKT/β-catenin pathway in glioma

Cell Death Dis. 2019 Jun 6;10(6):448. doi: 10.1038/s41419-019-1671-5.

Authors

Yan Chen^{1

2}, Xubin Deng³, Weiquan Chen, Pengwei Shi⁴, Mei Lian², Hongxiao Wang¹, Kewan Wang¹, Dadi Qian¹, Dong Xiao⁵, Hao Long⁶

Affiliations

¹ Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.
² Guangdong Provincial Key Laboratory of Cancer Immunotherapy Research and Guangzhou Key Laboratory of Tumor Immunology Research, Cancer Research Institute, Southern Medical University, Guangzhou, China.
³ Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China.
⁴ Department of Emergency, Nanfang Hospital, Southern Medical University, Guangzhou, China.
⁵ Guangdong Provincial Key Laboratory of Cancer Immunotherapy Research and Guangzhou Key Laboratory of Tumor Immunology Research, Cancer Research Institute, Southern Medical University, Guangzhou, China. Xiao_d@hotmail.com.
⁶ Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, China. longh812@163.com.

Abstract

Aberrant microRNA-708 (miR-708) expression is frequently reported in cancer studies; however, its role in glioma has not been examined in detail. We investigated miR-708 function in glioma and revealed that miR-708 expression was significantly down-regulated in glioma tissues and cell lines. Restoration of miR-708 inhibited glioma cell growth and invasion both in vitro and in vivo. The oncogene SPHK2 (sphingosine kinase 2) was identified as a downstream target of miR-708 using luciferase and western blot assays. miR-708 inhibited AKT/β-catenin signaling, which is activated by SPHK2. In addition, we revealed that miR-708 was transcriptionally repressed by EZH2 (enhancer of zeste homolog 2)-induced histone H3 lysine 27 trimethylation and promoter methylation. In summary, our findings revealed that miR-708 is a glioma tumor suppressor and suggest that miR-708 is a potential therapeutic target for glioma patients.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Brain Neoplasms / enzymology
Brain Neoplasms / genetics
Brain Neoplasms / metabolism*
Cell Cycle / genetics
Cell Line, Tumor
Cell Proliferation / genetics
Down-Regulation
Epithelial-Mesenchymal Transition / genetics*
Gene Expression Regulation, Neoplastic / genetics
Glioma / enzymology
Glioma / genetics
Glioma / metabolism*
Glycogen Synthase Kinases / chemistry
Glycogen Synthase Kinases / metabolism
Histones / chemistry
Histones / metabolism
Humans
Methylation
Mice
Mice, Nude
MicroRNAs / genetics
MicroRNAs / metabolism*
Phosphorylation
Phosphotransferases (Alcohol Group Acceptor) / genetics
Phosphotransferases (Alcohol Group Acceptor) / metabolism*
Prognosis
Proto-Oncogene Proteins c-akt / chemistry
Proto-Oncogene Proteins c-akt / genetics
Proto-Oncogene Proteins c-akt / metabolism*
Signal Transduction / genetics
Transplantation, Heterologous
beta Catenin / genetics
beta Catenin / metabolism*

Substances

CTNNB1 protein, human
Histones
MIRN708 microRNA, human
MicroRNAs
beta Catenin
Phosphotransferases (Alcohol Group Acceptor)
sphingosine kinase 2, human
Glycogen Synthase Kinases
Proto-Oncogene Proteins c-akt