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Characterization of Functionally Associated miRNAs in Glioblastoma and their Engineering into Artificial Clusters for Gene Therapy
Published on: October 4, 2019
miR-101/METTL3 axis induces autophagy by interrupting FOXG1/EIF3J-AS1 binding in gliomas
Yaping Yan1, Shanshan Liu1, Ailing Luo1
1Department of Hematology and Oncology, Guangzhou Women and Children's Medical Center, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou Medical University, Guangzhou, China.
None:
The role of autophagy in glioma remains controversial, with long non-coding RNAs (lncRNAs) playing a crucial role in its regulation. N6-methyladenosine (m6A) modification influences lncRNA expression and function. Specifically, lncRNA EIF3J-AS1 acts as an oncogene in glioma, yet the mechanisms driving its upregulation remain unclear. This study demonstrates that EIF3J-AS1 expression is significantly elevated in glioblastoma multiforme (GBM) compared to low-grade glioma (LGG) and normal brain tissue. RNA sequencing (RNA-seq) identified EIF3J-AS1 as a target of the tumor suppressor miR-101, with functional assays showing its role in promoting glioma cell proliferation, inhibiting autophagy, and enhancing tumorigenesis in vivo. Methylated RNA immunoprecipitation (MeRIP) and bioinformatics analyses confirmed m6A modification of EIF3J-AS1, which correlates positively with the m6A methyltransferase METTL3 in glioma tissues. Mechanistically, METTL3 promotes m6A-dependent binding of EIF3J-AS1 to the transcription factor FOXG1. RNA-seq screening further identified macrophage migration inhibitory factor (MIF), an autophagy-promoting gene, as a downstream target of both METTL3 and EIF3J-AS1. Functional validation revealed that the METTL3/EIF3J-AS1/FOXG1 axis suppresses autophagy via MIF downregulation. Conversely, miR-101-mediated suppression of METTL3 disrupts EIF3J-AS1-FOXG1 binding, restoring MIF expression and promoting autophagy. These findings highlight EIF3J-AS1 and METTL3 as potential therapeutic targets, with disruption of EIF3J-AS1-FOXG1 interactions representing a novel autophagy-modulating strategy for glioma treatment.
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