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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
SPI1-induced downregulation of FTO promotes GBM progression by regulating pri-miR-10a processing in an m6A-dependent
Shouji Zhang1,2, Shulin Zhao1,2, Yanhua Qi1,2
1Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, Shandong 250012, China.
Abstract:
As one of the most common post-transcriptional modifications of mRNAs and noncoding RNAs, N6-methyladenosine (m6A) modification regulates almost every aspect of RNA metabolism. Evidence indicates that dysregulation of m6A modification and associated proteins contributes to glioblastoma (GBM) progression. However, the function of fat mass and obesity-associated protein (FTO), an m6A demethylase, has not been systematically and comprehensively explored in GBM. Here, we found that decreased FTO expression in clinical specimens correlated with higher glioma grades and poorer clinical outcomes. Functionally, FTO inhibited growth and invasion in GBM cells in vitro and in vivo. Mechanistically, FTO regulated the m6A modification of primary microRNA-10a (pri-miR-10a), which could be recognized by reader HNRNPA2B1, recruiting the microRNA microprocessor complex protein DGCR8 and mediating pri-miR-10a processing. Furthermore, the transcriptional activity of FTO was inhibited by the transcription factor SPI1, which could be specifically disrupted by the SPI1 inhibitor DB2313. Treatment with this inhibitor restored endogenous FTO expression and decreased GBM tumor burden, suggesting that FTO may serve as a novel prognostic indicator and therapeutic molecular target of GBM.
Insights
Fat mass and obesity-associated protein (FTO) inhibits glioblastoma growth and invasion. Restoring FTO levels via SPI1 inhibition offers a potential therapeutic strategy for glioblastoma.
Area of Science:
- Molecular Biology
- Cancer Research
- Epigenetics
Background:
- N6-methyladenosine (m6A) modification is crucial for RNA metabolism.
- Dysregulation of m6A pathways is implicated in glioblastoma (GBM) progression.
Purpose of the Study:
- To investigate the role of fat mass and obesity-associated protein (FTO), an m6A demethylase, in GBM.
- To explore FTO as a potential prognostic indicator and therapeutic target in GBM.
Main Methods:
- Analysis of FTO expression in clinical GBM specimens.
- In vitro and in vivo functional assays to assess FTO's role in GBM cell growth and invasion.
- Investigation of the molecular mechanism involving pri-miR-10a, HNRNPA2B1, DGCR8, and the transcription factor SPI1.
- Evaluation of the SPI1 inhibitor DB2313 in a GBM model.
Main Results:
- Decreased FTO expression correlates with higher glioma grade and poorer outcomes.
- FTO suppresses GBM cell growth and invasion.
- FTO regulates pri-miR-10a processing via the HNRNPA2B1-DGCR8 pathway.
- SPI1 inhibits FTO transcription; DB2313 disrupts this inhibition, restoring FTO and reducing tumor burden.
Conclusions:
- FTO acts as a tumor suppressor in GBM.
- FTO's regulatory pathway involving pri-miR-10a processing is critical in GBM.
- Targeting the SPI1-FTO axis with inhibitors like DB2313 shows therapeutic potential for GBM.
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