Proteomics

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Metabolic Regulation of the Epigenome Drives Lethal Infantile Ependymoma

ABSTRACT: PFA ependymomas are a lethal glial malignancy of the hindbrain found in babies and toddlers. Lacking any highly recurrent somatic mutations, PFAs have been proposed as a largely epigenetically driven tumor type. An almost complete lack of model systems has inhibited discovery of novel PFA therapies. Both in vitro and in vivo, the PFA hypoxic microenvironment controls the availability of specific metabolites to diminish histone methylation, and to increase both histone demethylation and acetylation at H3K27. PFA ependymoma initiates from a cell lineage in the first trimester of human development where there is a known hypoxic microenvironment. Unique to PFA cells, transient exposure to ambient oxygen results in irreversible cellular toxicity. PFA tumors exhibit a low basal level of H3K27me3, and paradoxically inhibition of H3K27 methylation shows significant and specific activity against PFA. Targeting metabolism and/or the epigenome presents a unique opportunity for rational therapy for infants with PFA ependymoma.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Eric Bonneil  

LAB HEAD: Michael D. Taylor

PROVIDER: PXD018191 | Pride | 2020-08-13

REPOSITORIES: Pride

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Metabolic Regulation of the Epigenome Drives Lethal Infantile Ependymoma.

Michealraj Kulandaimanuvel Antony KA   Kumar Sachin A SA   Kim Leo J Y LJY   Cavalli Florence M G FMG   Przelicki David D   Wojcik John B JB   Delaidelli Alberto A   Bajic Andrea A   Saulnier Olivier O   MacLeod Graham G   Vellanki Ravi N RN   Vladoiu Maria C MC   Guilhamon Paul P   Ong Winnie W   Lee John J Y JJY   Jiang Yanqing Y   Holgado Borja L BL   Rasnitsyn Alex A   Malik Ahmad A AA   Tsai Ricky R   Richman Cory M CM   Juraschka Kyle K   Haapasalo Joonas J   Wang Evan Y EY   De Antonellis Pasqualino P   Suzuki Hiromichi H   Farooq Hamza H   Balin Polina P   Kharas Kaitlin K   Van Ommeren Randy R   Sirbu Olga O   Rastan Avesta A   Krumholtz Stacey L SL   Ly Michelle M   Ahmadi Moloud M   Deblois Geneviève G   Srikanthan Dilakshan D   Luu Betty B   Loukides James J   Wu Xiaochong X   Garzia Livia L   Ramaswamy Vijay V   Kanshin Evgeny E   Sánchez-Osuna María M   El-Hamamy Ibrahim I   Coutinho Fiona J FJ   Prinos Panagiotis P   Singh Sheila S   Donovan Laura K LK   Daniels Craig C   Schramek Daniel D   Tyers Mike M   Weiss Samuel S   Stein Lincoln D LD   Lupien Mathieu M   Wouters Bradly G BG   Garcia Benjamin A BA   Arrowsmith Cheryl H CH   Sorensen Poul H PH   Angers Stephane S   Jabado Nada N   Dirks Peter B PB   Mack Stephen C SC   Agnihotri Sameer S   Rich Jeremy N JN   Taylor Michael D MD  

Cell 20200522 6

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). PF  ...[more]

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