| Literature DB >> 30392959 |
Qi Xie1, Tao P Wu2, Ryan C Gimple3, Zheng Li2, Briana C Prager4, Qiulian Wu1, Yang Yu5, Pengcheng Wang5, Yinsheng Wang5, David U Gorkin6, Cheng Zhang6, Alexis V Dowiak6, Kaixuan Lin2, Chun Zeng7, Yinghui Sui7, Leo J Y Kim3, Tyler E Miller8, Li Jiang1, Christine H Lee9, Zhi Huang10, Xiaoguang Fang10, Kui Zhai10, Stephen C Mack11, Maike Sander7, Shideng Bao10, Amber E Kerstetter-Fogle12, Andrew E Sloan12, Andrew Z Xiao13, Jeremy N Rich14.
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.Entities:
Keywords: DNA methylation; H3K9me3; N(6)-methyladenine; brain tumor; cancer stem cell; chromatin; epigenetics; glioblastoma; heterochromatin; neuro-oncology
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Year: 2018 PMID： 30392959 PMCID： PMC6433469 DOI： 10.1016/j.cell.2018.10.006
Source DB: PubMed Journal: Cell ISSN： 0092-8674 Impact factor: 41.582