[PDF][PDF] N6-methyladenine DNA modification in glioblastoma

Q Xie, TP Wu, RC Gimple, Z Li, BC Prager, Q Wu, Y Yu… - Cell, 2018 - cell.com
Cell, 2018cell.com
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 6-methyladenine (N 6-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 6-mA levels …
Summary
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.
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