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N-methyladenine DNA Modification in Glioblastoma

2018; Cell Press; Volume: 175; Issue: 5 Linguagem: Inglês

10.1016/j.cell.2018.10.006

1097-4172

Qi Xie, Tao Wu, Ryan C. Gimple, Zheng Li, Briana C. Prager, Qiulian Wu, Yang Yu, Pengcheng Wang, Yinsheng Wang, David U. Gorkin, Cheng Zhang, Alexis Dowiak, Kaixuan Lin, Chun Zeng, Yinghui Sui, Leo J.Y. Kim, Tyler E. Miller, Li Jiang, Christine Lee, Zhi Huang, Xiaoguang Fang, Kui Zhai, Stephen C. Mack, Maike Sander, Shideng Bao, Amber Kerstetter-Fogle, Andrew E. Sloan, Andrew Xiao, Jeremy N. Rich,

Genomics and Chromatin Dynamics

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.