METTL3 regulates mA methylation of PTCH1 and GLI2 in Sonic hedgehog signaling to promote tumor progression in SHH-medulloblastoma.
Zhi-Wei Zhang, Xufei Teng, Fu Zhao, Chunhui Ma, Jing Zhang, Ling-Feng Xiao, Yaning Wang, Mengqi Chang, Yongji Tian, Chunde Li, Zhang Zhang, Shuhui Song, Wei-Min Tong, Pinan Liu, Yamei Niu
Author Information
- Zhi-Wei Zhang: Department of Pathology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Neuroscience Center, Chinese Academy of Medical Sciences, Beijing 100005, China.
- Xufei Teng: National Genomics Data Center, Beijing Institute of Genomics, Chinese Academy of Sciences/China National Center for Bioinformation, Beijing 100101, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China.
- Fu Zhao: Department of Neural Reconstruction, Beijing Neurosurgical Institute, Capital Medical University, Beijing 100070, China; Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China.
- Chunhui Ma: Department of Pathology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Neuroscience Center, Chinese Academy of Medical Sciences, Beijing 100005, China.
- Jing Zhang: Department of Neural Reconstruction, Beijing Neurosurgical Institute, Capital Medical University, Beijing 100070, China.
- Ling-Feng Xiao: Department of Pathology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Neuroscience Center, Chinese Academy of Medical Sciences, Beijing 100005, China.
- Yaning Wang: Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China.
- Mengqi Chang: Department of Pathology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Neuroscience Center, Chinese Academy of Medical Sciences, Beijing 100005, China.
- Yongji Tian: Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China.
- Chunde Li: Department of Neural Reconstruction, Beijing Neurosurgical Institute, Capital Medical University, Beijing 100070, China; Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China.
- Zhang Zhang: National Genomics Data Center, Beijing Institute of Genomics, Chinese Academy of Sciences/China National Center for Bioinformation, Beijing 100101, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China.
- Shuhui Song: National Genomics Data Center, Beijing Institute of Genomics, Chinese Academy of Sciences/China National Center for Bioinformation, Beijing 100101, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: songshh@big.ac.cn.
- Wei-Min Tong: Department of Pathology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Neuroscience Center, Chinese Academy of Medical Sciences, Beijing 100005, China; Molecular Pathology Research Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China. Electronic address: wmtong@ibms.pumc.edu.cn.
- Pinan Liu: Department of Neural Reconstruction, Beijing Neurosurgical Institute, Capital Medical University, Beijing 100070, China; Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China. Electronic address: pinanliu@ccmu.edu.cn.
- Yamei Niu: Department of Pathology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Neuroscience Center, Chinese Academy of Medical Sciences, Beijing 100005, China; Molecular Pathology Research Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China. Electronic address: niuym@ibms.pumc.edu.cn.
SHH subgroup medulloblastoma (SHH-MB) is one of the most common malignant pediatric tumors that arises in the cerebellum. Previously, we showed that RNA mA methylation participates in regulation of cerebellar development. Here we investigate whether dysregulated mA methylation contributes to tumorigenesis of SHH-MB. We show that high expression of mA methyltransferase METTL3 associates with worse survival in the patients with SHH-MB. A large number of hypermethylated transcripts are identified in SHH-MB tumor cells by mA-seq. We find that METTL3 promotes tumor progression via activating Sonic hedgehog signaling. Mechanistically, METTL3 methylates PTCH1 and GLI2 RNAs and further regulates their RNA stability and translation. Importantly, targeting METTL3 by depleting METTL3 expression or treatment with its catalytic inhibitor STM2457 restrains tumor progression. Collectively, this study shows a critical function for METTL3 and mA methylation in SHH-MB, indicative of a potential role of METTL3 as therapeutic target in SHH-MB.
Child
Humans
Cerebellar Neoplasms
Hedgehog Proteins
Medulloblastoma
Methylation
Methyltransferases
Nuclear Proteins
RNA
Zinc Finger Protein Gli2
GLI2 protein, human
Hedgehog Proteins
Methyltransferases
METTL3 protein, human
Nuclear Proteins
RNA
SHH protein, human
Zinc Finger Protein Gli2
PTCH1 protein, human
