Molecular Therapy: Nucleic Acids (Mar 2022)
SPI1-induced downregulation of FTO promotes GBM progression by regulating pri-miR-10a processing in an m6A-dependent manner
- Shouji Zhang,
- Shulin Zhao,
- Yanhua Qi,
- Boyan Li,
- Huizhi Wang,
- Ziwen Pan,
- Hao Xue,
- Chuandi Jin,
- Wei Qiu,
- Zihang Chen,
- Qindong Guo,
- Yang Fan,
- Jianye Xu,
- Zijie Gao,
- Shaobo Wang,
- Xing Guo,
- Lin Deng,
- Shilei Ni,
- Fuzhong Xue,
- Jian Wang,
- Rongrong Zhao,
- Gang Li
Affiliations
- Shouji Zhang
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, Shandong 250012, China; Shandong Key Laboratory of Brain Function Remodeling, Jinan, Shandong 250012, China
- Shulin Zhao
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, Shandong 250012, China; Shandong Key Laboratory of Brain Function Remodeling, Jinan, Shandong 250012, China
- Yanhua Qi
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, Shandong 250012, China; Shandong Key Laboratory of Brain Function Remodeling, Jinan, Shandong 250012, China
- Boyan Li
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, Shandong 250012, China; Shandong Key Laboratory of Brain Function Remodeling, Jinan, Shandong 250012, China
- Huizhi Wang
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, Shandong 250012, China; Shandong Key Laboratory of Brain Function Remodeling, Jinan, Shandong 250012, China
- Ziwen Pan
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, Shandong 250012, China; Shandong Key Laboratory of Brain Function Remodeling, Jinan, Shandong 250012, China
- Hao Xue
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, Shandong 250012, China; Shandong Key Laboratory of Brain Function Remodeling, Jinan, Shandong 250012, China
- Chuandi Jin
- Institute for Medical Dataology of Shandong University, Jinan, People’s Republic of China; Department of Epidemiology and Health Statistics, School of Public Health, Shandong University, Jinan, Shandong Province, People’s Republic of China
- Wei Qiu
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, Shandong 250012, China; Shandong Key Laboratory of Brain Function Remodeling, Jinan, Shandong 250012, China
- Zihang Chen
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, Shandong 250012, China; Shandong Key Laboratory of Brain Function Remodeling, Jinan, Shandong 250012, China
- Qindong Guo
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, Shandong 250012, China; Shandong Key Laboratory of Brain Function Remodeling, Jinan, Shandong 250012, China
- Yang Fan
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, Shandong 250012, China; Shandong Key Laboratory of Brain Function Remodeling, Jinan, Shandong 250012, China
- Jianye Xu
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, Shandong 250012, China; Shandong Key Laboratory of Brain Function Remodeling, Jinan, Shandong 250012, China
- Zijie Gao
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, Shandong 250012, China; Shandong Key Laboratory of Brain Function Remodeling, Jinan, Shandong 250012, China
- Shaobo Wang
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, Shandong 250012, China; Shandong Key Laboratory of Brain Function Remodeling, Jinan, Shandong 250012, China
- Xing Guo
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, Shandong 250012, China; Shandong Key Laboratory of Brain Function Remodeling, Jinan, Shandong 250012, China
- Lin Deng
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, Shandong 250012, China; Shandong Key Laboratory of Brain Function Remodeling, Jinan, Shandong 250012, China
- Shilei Ni
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, Shandong 250012, China; Shandong Key Laboratory of Brain Function Remodeling, Jinan, Shandong 250012, China
- Fuzhong Xue
- Institute for Medical Dataology of Shandong University, Jinan, People’s Republic of China; Department of Epidemiology and Health Statistics, School of Public Health, Shandong University, Jinan, Shandong Province, People’s Republic of China
- Jian Wang
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, Shandong 250012, China; Shandong Key Laboratory of Brain Function Remodeling, Jinan, Shandong 250012, China; Department of Biomedicine, University of Bergen, Jonas Lies Vei 91, 5009 Bergen, Norway
- Rongrong Zhao
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, Shandong 250012, China; Shandong Key Laboratory of Brain Function Remodeling, Jinan, Shandong 250012, China; Corresponding author: Rongrong Zhao, Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan 250012, Shandong, China.
- Gang Li
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, Shandong 250012, China; Shandong Key Laboratory of Brain Function Remodeling, Jinan, Shandong 250012, China; Corresponding author: Gang Li, Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan 250012, Shandong, China.
- Journal volume & issue
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Vol. 27
pp. 699 – 717
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.
