2. Academic Validation
  3. METTL3 regulates m6A methylation of PTCH1 and GLI2 in Sonic hedgehog signaling to promote tumor progression in SHH-medulloblastoma

METTL3 regulates m6A methylation of PTCH1 and GLI2 in Sonic hedgehog signaling to promote tumor progression in SHH-medulloblastoma

  • Cell Rep. 2022 Oct 25;41(4):111530. doi: 10.1016/j.celrep.2022.111530.
Zhi-Wei Zhang 1,  Xufei Teng 2,  Fu Zhao 3,  Chunhui Ma 1,  Jing Zhang 4,  Ling-Feng Xiao 1,  Yaning Wang 5,  Mengqi Chang 1,  Yongji Tian 6,  Chunde Li 3,  Zhang Zhang 2,  Shuhui Song 7,  Wei-Min Tong 8,  Pinan Liu 9,  Yamei Niu 10
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 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.
  • 4 Department of Neural Reconstruction, Beijing Neurosurgical Institute, Capital Medical University, Beijing 100070, China.
  • 5 Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China.
  • 6 Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China.
  • 7 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.
  • 8 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.
  • 9 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.
  • 10 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.
PMID: 36288719 DOI: 10.1016/j.celrep.2022.111530
Abstract

SHH subgroup medulloblastoma (SHH-MB) is one of the most common malignant pediatric tumors that arises in the cerebellum. Previously, we showed that RNA m6A methylation participates in regulation of cerebellar development. Here we investigate whether dysregulated m6A methylation contributes to tumorigenesis of SHH-MB. We show that high expression of m6A 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 m6A-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 m6A methylation in SHH-MB, indicative of a potential role of METTL3 as therapeutic target in SHH-MB.

Keywords

CP: Cancer; CP: Molecular biology; METTL3; RNA m(6)A methylation; hedgehog signaling pathway; medulloblastoma.

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