N 6-methyladenine DNA Modification in Glioblastoma

Cell. 2018 Nov 15;175(5):1228-1243.e20. doi: 10.1016/j.cell.2018.10.006. Epub 2018 Nov 1.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenine / analogs & derivatives*
  • Adenine / analysis
  • Adenine / chemistry
  • Adult
  • Aged
  • AlkB Homolog 1, Histone H2a Dioxygenase / antagonists & inhibitors
  • AlkB Homolog 1, Histone H2a Dioxygenase / genetics
  • AlkB Homolog 1, Histone H2a Dioxygenase / metabolism
  • Animals
  • Astrocytes / cytology
  • Astrocytes / metabolism
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / mortality
  • Brain Neoplasms / pathology*
  • Cell Hypoxia
  • Child
  • DNA Methylation*
  • Epigenomics
  • Female
  • Glioblastoma / metabolism
  • Glioblastoma / mortality
  • Glioblastoma / pathology*
  • Heterochromatin / metabolism
  • Histones / metabolism
  • Humans
  • Kaplan-Meier Estimate
  • Male
  • Mice
  • Middle Aged
  • Neoplastic Stem Cells / cytology
  • Neoplastic Stem Cells / metabolism
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Heterochromatin
  • Histones
  • RNA, Small Interfering
  • Tumor Suppressor Protein p53
  • ALKBH1 protein, human
  • AlkB Homolog 1, Histone H2a Dioxygenase
  • Adenine
  • 6-methyladenine