2. Academic Validation
  3. Argininosuccinate lyase drives activation of mutant TERT promoter in glioblastomas

Argininosuccinate lyase drives activation of mutant TERT promoter in glioblastomas

  • Mol Cell. 2022 Oct 20;82(20):3919-3931.e7. doi: 10.1016/j.molcel.2022.09.024.
Zhumei Shi 1,  Xin Ge 2,  Mengdie Li 2,  Jianxing Yin 1,  Xiefeng Wang 1,  Junxia Zhang 1,  Dongyin Chen 3,  Xinjian Li 4,  Xiuxing Wang 5,  Jing Ji 1,  Yongping You 6,  Xu Qian 7
Affiliations

Affiliations

  • 1 Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China; Institute for Brain Tumors, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu 211166, China.
  • 2 Institute for Brain Tumors, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu 211166, China; Department of Nutrition and Food Hygiene, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China.
  • 3 Department of Medicinal Chemistry, School of Pharmacy, Nanjing Medical University, Nanjing, Jiangsu 211166, China.
  • 4 CAS Key Laboratory of Infection and Immunity, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
  • 5 National Health Commission Key Laboratory of Antibody Technologies, Nanjing Medical University, Nanjing, Jiangsu 211166, China; Department of Cell Biology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu 211166, China.
  • 6 Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China; Institute for Brain Tumors, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu 211166, China. Electronic address: yypl9@njmu.edu.cn.
  • 7 Institute for Brain Tumors, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu 211166, China; Department of Nutrition and Food Hygiene, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China; Jiangsu Cancer Hospital, Nanjing Medical University Affiliated Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing, Jiangsu 210009, China. Electronic address: xqianmedres@njmu.edu.cn.
PMID: 36270249 DOI: 10.1016/j.molcel.2022.09.024
Abstract

Cancer-specific TERT promoter mutations have been linked to the reactivation of epigenetically silenced TERT gene by creating de novo binding motifs for E-Twenty-Six transcription factors, especially GABPA. How these mutations switch on TERT from epigenetically repressed states to expressed states have not been defined. Here, we revealed that EGFR activation induces ERK1/2-dependent phosphorylation of argininosuccinate lyase (ASL) at Ser417 (S417), leading to interactions between ASL and GABPA at the mutant regions of TERT promoters. The ASL-generated fumarate inhibits KDM5C, leading to enhanced trimethylation of histone H3 Lys4 (H3K4me3), which in turn promotes the recruitment of c-Myc to TERT promoters for TERT expression. Expression of ASL S417A, which abrogates its binding with GABPA, results in reduced TERT expression, inhibited Telomerase activity, shortened telomere length, and impaired brain tumor growth in mice. This study reveals an unrecognized mechanistic insight into epigenetically activation of mutant TERT promoters where GABPA-interacted ASL plays an instrumental role.

Keywords

GABPA; H3K4me3; TERT; argininosuccinate lyase; c-Myc; fumarate; glioblastoma; metabolism; phosphorylation; telomerase.

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