2. Academic Validation
  3. N6-methyladenine DNA Modification in Glioblastoma

N6-methyladenine DNA Modification in Glioblastoma

  • Cell. 2018 Nov 15;175(5):1228-1243.e20. doi: 10.1016/j.cell.2018.10.006.
Qi Xie 1,  Tao P Wu 2,  Ryan C Gimple 3,  Zheng Li 2,  Briana C Prager 4,  Qiulian Wu 1,  Yang Yu 5,  Pengcheng Wang 5,  Yinsheng Wang 5,  David U Gorkin 6,  Cheng Zhang 6,  Alexis V Dowiak 6,  Kaixuan Lin 2,  Chun Zeng 7,  Yinghui Sui 7,  Leo J Y Kim 3,  Tyler E Miller 8,  Li Jiang 1,  Christine H Lee 9,  Zhi Huang 10,  Xiaoguang Fang 10,  Kui Zhai 10,  Stephen C Mack 11,  Maike Sander 7,  Shideng Bao 10,  Amber E Kerstetter-Fogle 12,  Andrew E Sloan 12,  Andrew Z Xiao 13,  Jeremy N Rich 14
Affiliations

Affiliations

  • 1 Department of Medicine, Division of Regenerative Medicine, University of California, San Diego, La Jolla, CA 92037, USA.
  • 2 Department of Genetics and Yale Stem Cell Center, Yale School of Medicine, New Haven, CT 06520, USA.
  • 3 Department of Medicine, Division of Regenerative Medicine, University of California, San Diego, La Jolla, CA 92037, USA; Department of Pathology, Case Western Reserve University, Cleveland, OH 44120, USA.
  • 4 Department of Medicine, Division of Regenerative Medicine, University of California, San Diego, La Jolla, CA 92037, USA; Department of Pathology, Case Western Reserve University, Cleveland, OH 44120, USA; Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44195, USA.
  • 5 Department of Chemistry, University of California, Riverside, Riverside, CA 92521, USA.
  • 6 Center for Epigenomics, Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92037, USA.
  • 7 Departments of Pediatrics and Cellular and Molecular Medicine, Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA, 92093, USA.
  • 8 Department of Pathology, Case Western Reserve University, Cleveland, OH 44120, USA.
  • 9 Department of Pharmacology, Case Western Reserve University, Cleveland, OH 44195, USA.
  • 10 Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
  • 11 Department of Pediatrics, Division of Hematology and Oncology, Baylor College of Medicine, Texas Children's Hospital, Houston, TX 77030, USA.
  • 12 Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA; Department of Neurological Surgery, University Hospitals - Cleveland Medical Center, Cleveland, OH 44106, USA.
  • 13 Department of Genetics and Yale Stem Cell Center, Yale School of Medicine, New Haven, CT 06520, USA. Electronic address: andrew.xiao@yale.edu.
  • 14 Department of Medicine, Division of Regenerative Medicine, University of California, San Diego, La Jolla, CA 92037, USA; Department of Neurosciences, University of California, San Diego, School of Medicine, La Jolla, CA 92037, USA. Electronic address: drjeremyrich@gmail.com.
PMID: 30392959 DOI: 10.1016/j.cell.2018.10.006
Abstract

Genetic drivers of Cancer can be dysregulated through epigenetic modifications of DNA. Although the critical role of DNA 5-methylcytosine (5mC) in the regulation of transcription is recognized, the functions of other non-canonical DNA modifications remain obscure. Here, we report the identification of novel N6-methyladenine (N6-mA) DNA modifications in human tissues and implicate this epigenetic mark in human disease, specifically the highly malignant brain Cancer glioblastoma. Glioblastoma markedly upregulated N6-mA levels, which co-localized with heterochromatic histone modifications, predominantly H3K9me3. N6-mA levels were dynamically regulated by the DNA demethylase ALKBH1, depletion of which led to transcriptional silencing of oncogenic pathways through decreasing chromatin accessibility. Targeting the N6-mA regulator ALKBH1 in patient-derived human glioblastoma models inhibited tumor cell proliferation and extended the survival of tumor-bearing mice, supporting this novel DNA modification as a potential therapeutic target for glioblastoma. Collectively, our results uncover a novel epigenetic node in Cancer through the DNA modification N6-mA.

Keywords

DNA methylation; H3K9me3; N(6)-methyladenine; brain tumor; cancer stem cell; chromatin; epigenetics; glioblastoma; heterochromatin; neuro-oncology.

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