N<sup>6</sup>-methyladenine DNA Modification in Glioblastoma.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 30392959.
- Also identified by DOI 10.1016/j.cell.2018.10.006 and PMC identifier 6433469.
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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 N<sup>6</sup>-methyladenine (N<sup>6</sup>-mA) DNA modifications in human tissues and implicate this epigenetic mark in human disease, specifically the highly malignant brain cancer glioblastoma. Glioblastoma markedly upregulated N<sup>6</sup>-mA levels, which co-localized with heterochromatic histone modifications, predominantly H3K9me3. N<sup>6</sup>-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 N<sup>6</sup>-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 N<sup>6</sup>-mA.
Medical subject headings
- Adenine
- Brain Neoplasms
- DNA Methylation
- Glioblastoma