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N(6)-methyladenine DNA modification in glioblastoma

Item Type:Article
Title:N(6)-methyladenine DNA modification in glioblastoma
Creators Name:Xie, Q. and Wu, T.P. and Gimple, R.C. and Li, Z. and Prager, B.C. and Wu, Q. and Yu, Y. and Wang, P. and Wang, Y. and Gorkin, D.U. and Zhang, C. and Dowiak, A.V. and Lin, K. and Zeng, C. and Sui, Y. and Kim, L.J.Y. and Miller, T.E. and Jiang, L. and Lee, C.H. and Huang, Z. and Fang, X.. and Zhai, K. and Mack, S.C. and Sander, M. and Bao, S. and Kerstetter-Fogle, A.E. and Sloan, A.E. and Xiao, A.Z. and Rich, J.N.
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(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, which co-localized with heterochromatic histone modifications, predominantly H3K9me3. N(6)-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(6)-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(6)-mA.
Keywords:DNA Methylation, N6-Methyladenine, Glioblastoma, Epigenetics, Cancer Stem Cell, Chromatin, Heterochromatin, Neuro-Oncology, Brain Tumor, H3K9me3, Animals, Mice
Publisher:Cell Press
Page Range:1228-1243
Date:15 November 2018
Official Publication:https://doi.org/10.1016/j.cell.2018.10.006
PubMed:View item in PubMed

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