2. Academic Validation
  3. METTL8 links mt-tRNA m3C modification to the HIF1α/RTK/Akt axis to sustain GBM stemness and tumorigenicity

METTL8 links mt-tRNA m3C modification to the HIF1α/RTK/Akt axis to sustain GBM stemness and tumorigenicity

  • Cell Death Dis. 2024 May 14;15(5):338. doi: 10.1038/s41419-024-06718-2.
Bernice Woon Li Lee # 1 2,  You Heng Chuah # 1 2,  Jeehyun Yoon # 1 2,  Oleg V Grinchuk # 1 2,  Yajing Liang 1,  Jayshree L Hirpara 3,  Yating Shen 4 5,  Loo Chien Wang 6,  Yan Ting Lim 6,  Tianyun Zhao 6,  Radoslaw M Sobota 6,  Tseng Tsai Yeo 7,  Andrea Li Ann Wong 3 8,  Kejia Teo 7,  Vincent Diong Weng Nga 7,  Bryce Wei Quan Tan 9,  Toshio Suda 3 10,  Tan Boon Toh 4 5,  Shazib Pervaiz 1 2 11,  Zhewang Lin 12,  Derrick Sek Tong Ong 13 14 15 16
Affiliations

Affiliations

  • 1 Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117593, Singapore.
  • 2 NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
  • 3 Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore.
  • 4 The N.1 Institute for Health, National University of Singapore, Singapore, Singapore.
  • 5 The Institute for Digital Medicine (WisDM), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
  • 6 Functional Proteomics Laboratory, SingMass National Laboratory, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
  • 7 Department of Surgery, Division of Neurosurgery, National University Hospital, Singapore, Singapore.
  • 8 Department of Haematology-Oncology, National University Hospital, Singapore, Singapore.
  • 9 Department of Medicine, National University Hospital, Singapore, Singapore.
  • 10 International Research Center for Medical Sciences, Kumamoto University, Kumamoto, 860-0811, Japan.
  • 11 Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
  • 12 Department of Biological Sciences, 14 Science Drive 4, National University of Singapore, 117543, Singapore, Singapore.
  • 13 Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117593, Singapore. phsostd@nus.edu.sg.
  • 14 NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. phsostd@nus.edu.sg.
  • 15 Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore. phsostd@nus.edu.sg.
  • 16 National Neuroscience Institute, 308433, Singapore, Singapore. phsostd@nus.edu.sg.
  • # Contributed equally.
PMID: 38744809 DOI: 10.1038/s41419-024-06718-2
Abstract

Epitranscriptomic RNA modifications are crucial for the maintenance of glioma stem cells (GSCs), the most malignant cells in glioblastoma (GBM). 3-methylcytosine (m3C) is a new epitranscriptomic mark on RNAs and METTL8 represents an m3C writer that is dysregulated in Cancer. Although METTL8 has an established function in mitochondrial tRNA (mt-tRNA) m3C modification, alternative splicing of METTL8 can also generate isoforms that localize to the nucleolus where they may regulate R-loop formation. The molecular basis for METTL8 dysregulation in GBM, and which METTL8 isoform(s) may influence GBM cell fate and malignancy remain elusive. Here, we investigated the role of METTL8 in regulating GBM stemness and tumorigenicity. In GSC, METTL8 is exclusively localized to the mitochondrial matrix where it installs m3C on mt-tRNAThr/Ser(UCN) for mitochondrial translation and respiration. High expression of METTL8 in GBM is attributed to histone variant H2AZ-mediated chromatin accessibility of HIF1α and portends inferior glioma patient outcome. METTL8 depletion impairs the ability of GSC to self-renew and differentiate, thus retarding tumor growth in an intracranial GBM xenograft model. Interestingly, METTL8 depletion decreases protein levels of HIF1α, which serves as a transcription factor for several receptor tyrosine kinase (RTK) genes, in GSC. Accordingly, METTL8 loss inactivates the RTK/Akt axis leading to heightened sensitivity to Akt Inhibitor treatment. These mechanistic findings, along with the intimate link between METTL8 levels and the HIF1α/RTK/Akt axis in glioma patients, guided us to propose a HIF1α/Akt Inhibitor combination which potently compromises GSC proliferation/self-renewal in vitro. Thus, METTL8 represents a new GBM dependency that is therapeutically targetable.

Figures
Products