Metabolic Regulation of the Epigenome Drives Lethal Infantile Ependymoma
| Autor: | Samuel Weiss, Leo J.Y. Kim, Xiaochong Wu, Randy Van Ommeren, Yanqing Jiang, Kaitlin Kharas, Evgeny Kanshin, Moloud Ahmadi, Alberto Delaidelli, Geneviève Deblois, David Przelicki, Stephane Angers, Hiromichi Suzuki, Sameer Agnihotri, Bradly G. Wouters, Graham MacLeod, Ricky Tsai, Pasqualino De Antonellis, Michelle Ly, Stacey L. Krumholtz, Paul Guilhamon, James Loukides, Ravi N. Vellanki, Alex Rasnitsyn, Hamza Farooq, Daniel Schramek, Nada Jabado, María Sánchez-Osuna, Laura K. Donovan, Vijay Ramaswamy, Ibrahim El-Hamamy, Joonas Haapasalo, Jeremy N. Rich, Michael D. Taylor, Benjamin A. Garcia, Mike Tyers, Kyle Juraschka, Winnie Ong, Olivier Saulnier, Panagiotis Prinos, John J.Y. Lee, Borja L. Holgado, Olga Sirbu, Craig Daniels, Cheryl H. Arrowsmith, Cory Richman, Poul H. Sorensen, Kulandaimanuvel Antony Michealraj, Sheila K. Singh, Andrea Bajic, Polina Balin, Stephen C. Mack, Betty Luu, Fiona J. Coutinho, Dilakshan Srikanthan, Florence M.G. Cavalli, Sachin Kumar, Evan Y. Wang, Mathieu Lupien, Peter B. Dirks, Maria C. Vladoiu, Lincoln Stein, Livia Garzia, Ahmad Malik, John Wojcik, Avesta Rastan |
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| Přispěvatelé: | Michealraj, K. A., Kumar, S. A., Kim, L. J. Y., Cavalli, F. M. G., Przelicki, D., Wojcik, J. B., Delaidelli, A., Bajic, A., Saulnier, O., Macleod, G., Vellanki, R. N., Vladoiu, M. C., Guilhamon, P., Ong, W., Lee, J. J. Y., Jiang, Y., Holgado, B. L., Rasnitsyn, A., Malik, A. A., Tsai, R., Richman, C. M., Juraschka, K., Haapasalo, J., Wang, E. Y., De Antonellis, P., Suzuki, H., Farooq, H., Balin, P., Kharas, K., Van Ommeren, R., Sirbu, O., Rastan, A., Krumholtz, S. L., Ly, M., Ahmadi, M., Deblois, G., Srikanthan, D., Luu, B., Loukides, J., Wu, X., Garzia, L., Ramaswamy, V., Kanshin, E., Sanchez-Osuna, M., El-Hamamy, I., Coutinho, F. J., Prinos, P., Singh, S., Donovan, L. K., Daniels, C., Schramek, D., Tyers, M., Weiss, S., Stein, L. D., Lupien, M., Wouters, B. G., Garcia, B. A., Arrowsmith, C. H., Sorensen, P. H., Angers, S., Jabado, N., Dirks, P. B., Mack, S. C., Agnihotri, S., Rich, J. N., Taylor, M. D. |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Epigenomics
Ependymoma Male ependymoma Epigenomic Somatic cell cancer metabolism Infratentorial Neoplasms Biology General Biochemistry Genetics and Molecular Biology Cell Line Histones Brain Neoplasm 03 medical and health sciences Epigenome 0302 clinical medicine Histone demethylation Histone methylation medicine Animals Humans Epigenetics 030304 developmental biology hindbrain development Cell Proliferation Infratentorial Neoplasm 0303 health sciences Brain Neoplasms Animal Lysine Infant DNA Methylation medicine.disease microenvironment Mice Inbred C57BL Histone Acetylation paediatric cancer Mutation biology.protein Cancer research 030217 neurology & neurosurgery epigenetic Human |
| Popis: | 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. Hypoxia reprograms the cellular metabolome and epigenome to promote growth of the most lethal ependymomas. |
| Databáze: | OpenAIRE |
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