| Literature DB >> 32445698 |
Kulandaimanuvel Antony Michealraj1, Sachin A Kumar2, Leo J Y Kim3, Florence M G Cavalli1, David Przelicki2, John B Wojcik4, Alberto Delaidelli5, Andrea Bajic6, Olivier Saulnier1, Graham MacLeod7, Ravi N Vellanki8, Maria C Vladoiu2, Paul Guilhamon1, Winnie Ong2, John J Y Lee2, Yanqing Jiang1, Borja L Holgado1, Alex Rasnitsyn9, Ahmad A Malik10, Ricky Tsai11, Cory M Richman9, Kyle Juraschka2, Joonas Haapasalo1, Evan Y Wang9, Pasqualino De Antonellis1, Hiromichi Suzuki1, Hamza Farooq1, Polina Balin2, Kaitlin Kharas2, Randy Van Ommeren2, Olga Sirbu9, Avesta Rastan1, Stacey L Krumholtz1, Michelle Ly2, Moloud Ahmadi7, Geneviève Deblois8, Dilakshan Srikanthan2, Betty Luu1, James Loukides1, Xiaochong Wu1, Livia Garzia12, Vijay Ramaswamy13, Evgeny Kanshin14, María Sánchez-Osuna14, Ibrahim El-Hamamy15, Fiona J Coutinho1, Panagiotis Prinos16, Sheila Singh17, Laura K Donovan1, Craig Daniels1, Daniel Schramek10, Mike Tyers14, Samuel Weiss18, Lincoln D Stein15, Mathieu Lupien8, Bradly G Wouters8, Benjamin A Garcia4, Cheryl H Arrowsmith19, Poul H Sorensen5, Stephane Angers20, Nada Jabado21, Peter B Dirks22, Stephen C Mack23, Sameer Agnihotri24, Jeremy N Rich25, Michael D Taylor26.
Abstract
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.Entities:
Keywords: cancer metabolism; ependymoma; epigenetics; hindbrain development; microenvironment; paediatric cancer
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Year: 2020 PMID： 32445698 DOI： 10.1016/j.cell.2020.04.047
Source DB: PubMed Journal: Cell ISSN： 0092-8674 Impact factor: 66.850