Metabolic Regulation of the Epigenome Drives Lethal Infantile Ependymoma.,Cell

当前位置： X-MOL 学术 › Cell › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Metabolic Regulation of the Epigenome Drives Lethal Infantile Ependymoma.
Cell ( IF 64.5 ) Pub Date : 2020-05-22 , DOI: 10.1016/j.cell.2020.04.047
Kulandaimanuvel Antony Michealraj ₁ , Sachin A Kumar ₂ , Leo J Y Kim ₃ , Florence M G Cavalli ₁ , David Przelicki ₂ , John B Wojcik ₄ , Alberto Delaidelli ₅ , Andrea Bajic ₆ , Olivier Saulnier ₁ , Graham MacLeod ₇ , Ravi N Vellanki ₈ , Maria C Vladoiu ₂ , Paul Guilhamon ₁ , Winnie Ong ₂ , John J Y Lee ₂ , Yanqing Jiang ₁ , Borja L Holgado ₁ , Alex Rasnitsyn ₉ , Ahmad A Malik ₁₀ , Ricky Tsai ₁₁ , Cory M Richman ₉ , Kyle Juraschka ₂ , Joonas Haapasalo ₁ , Evan Y Wang ₉ , Pasqualino De Antonellis ₁ , Hiromichi Suzuki ₁ , Hamza Farooq ₁ , Polina Balin ₂ , Kaitlin Kharas ₂ , Randy Van Ommeren ₂ , Olga Sirbu ₉ , Avesta Rastan ₁ , Stacey L Krumholtz ₁ , Michelle Ly ₂ , Moloud Ahmadi ₇ , Geneviève Deblois ₈ , Dilakshan Srikanthan ₂ , Betty Luu ₁ , James Loukides ₁ , Xiaochong Wu ₁ , Livia Garzia ₁₂ , Vijay Ramaswamy ₁₃ , Evgeny Kanshin ₁₄ , María Sánchez-Osuna ₁₄ , Ibrahim El-Hamamy ₁₅ , Fiona J Coutinho ₁ , Panagiotis Prinos ₁₆ , Sheila Singh ₁₇ , Laura K Donovan ₁ , Craig Daniels ₁ , Daniel Schramek ₁₀ , Mike Tyers ₁₄ , Samuel Weiss ₁₈ , Lincoln D Stein ₁₅ , Mathieu Lupien ₈ , Bradly G Wouters ₈ , Benjamin A Garcia ₄ , Cheryl H Arrowsmith ₁₉ , Poul H Sorensen ₅ , Stephane Angers ₂₀ , Nada Jabado ₂₁ , Peter B Dirks ₂₂ , Stephen C Mack ₂₃ , Sameer Agnihotri ₂₄ , Jeremy N Rich ₃ , Michael D Taylor ₂₅

Affiliation

The Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
The Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5G 1L7, Canada.
Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA 92037, USA.
Department of Biochemistry and Biophysics and Penn Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, BC V6T 1Z2, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6T 1Z2, Canada.
Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada.
Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON M5S 3M2, Canada.
Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada.
The Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada.
Centre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1L7, Canada.
Centre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.
Cancer Research Program, McGill University Health Centre Research Institute, Montreal, QC H4A 3J1, Canada.
The Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Division of Haematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
Institute for Research in Immunology and Cancer (IRIC), Department of Medicine, Université de Montréal, Montréal, QC H3C 3J7, Canada.
Computational Biology Program, Adaptive Oncology Theme, Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1L7, Canada.
Structural Genomics Consortium, University of Toronto, 101 College Street, MaRS Centre, South Tower, Toronto, ON M5G 1L7, Canada.
Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON L8S 4K1, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada; Department of Surgery, McMaster University, Hamilton, ON L8S 4K1, Canada.
Hotchkiss Brain Institute, Department of Cell Biology and Anatomy, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Structural Genomics Consortium, University of Toronto, 101 College Street, MaRS Centre, South Tower, Toronto, ON M5G 1L7, Canada.
Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON M5S 3M2, Canada; Department of Biochemistry, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada; Department of Pediatrics, McGill University, The Research Institute of the McGill University Health Center, Montreal, QC H4A 3J1, Canada.
The Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1L7, Canada; Division of Neurosurgery, The Hospital for Sick Children, Toronto, ON M5G 1L7, Canada.
Texas Children's Hospital Cancer Center, Department of Pediatrics, Baylor College of Medicine, Dan L. Duncan Cancer Center, Houston, TX 77030, USA.
Department of Neurological Surgery, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
The Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada; Division of Neurosurgery, The Hospital for Sick Children, Toronto, ON M5G 1L7, Canada.

Posterior fossa A (PFA) ependymomas are lethal malignancies of the hindbrain in infants and toddlers. Lacking highly recurrent somatic mutations, PFA ependymomas are proposed to be epigenetically driven tumors for which model systems are lacking. Here we demonstrate that PFA ependymomas are maintained under hypoxia, associated with restricted availability of specific metabolites to diminish histone methylation, and increase histone demethylation and acetylation at histone 3 lysine 27 (H3K27). PFA ependymomas initiate from a cell lineage in the first trimester of human development that resides in restricted oxygen. Unlike other ependymomas, transient exposure of PFA cells to ambient oxygen induces irreversible cellular toxicity. PFA tumors exhibit a low basal level of H3K27me3, and, paradoxically, inhibition of H3K27 methylation specifically disrupts PFA tumor growth. Targeting metabolism and/or the epigenome presents a unique opportunity for rational therapy for infants with PFA ependymoma.

中文翻译：

表观基因组的代谢调节导致致命的婴儿室管膜瘤。

A 后窝 (PFA) 室管膜瘤是婴儿和幼儿后脑的致命恶性肿瘤。由于缺乏高度复发的体细胞突变，PFA 室管膜瘤被认为是表观遗传驱动的肿瘤，缺乏模型系统。在这里，我们证明 PFA 室管膜瘤在缺氧下维持，与减少组蛋白甲基化和增加组蛋白 3 赖氨酸 27 (H3K27) 的组蛋白去甲基化和乙酰化的特定代谢物的可用性有限有关。PFA 室管膜瘤起源于人类发育前三个月的细胞谱系，该细胞谱系存在于受限的氧气中。与其他室管膜瘤不同，PFA 细胞短暂暴露于环境氧气会引起不可逆的细胞毒性。PFA 肿瘤表现出较低的 H3K27me3 基础水平，矛盾的是，抑制 H3K27 甲基化会特异性破坏 PFA 肿瘤的生长。针对代谢和/或表观基因组为 PFA 室管膜瘤婴儿的合理治疗提供了独特的机会。

更新日期：2020-05-22

点击分享查看原文

点击收藏

阅读更多本刊最新论文本刊介绍/投稿指南

全部期刊列表>>