| Literature DB >> 34613815 |
Pooja Panwalkar1, Benita Tamrazi2, Derek Dang1, Chan Chung3, Stefan Sweha1, Siva Kumar Natarajan1, Matthew Pun1, Jill Bayliss1, Martin P Ogrodzinski4,5, Drew Pratt1, Brendan Mullan6, Debra Hawes7, Fusheng Yang7, Chao Lu8, Benjamin R Sabari9, Abhinav Achreja10,11, Jin Heon10,11, Olamide Animasahun10,11,12, Marcin Cieslik1, Christopher Dunham13,14, Stephen Yip14, Juliette Hukin15, Joanna J Phillips16,17, Miriam Bornhorst18,19, Andrea M Griesinger20,21, Andrew M Donson20,21, Nicholas K Foreman21,22, Hugh J L Garton22, Jason Heth22, Karin Muraszko22, Javad Nazarian18,19,23, Carl Koschmann6, Li Jiang24, Mariella G Filbin24, Deepak Nagrath10,11, Marcel Kool25,26,27, Andrey Korshunov28, Stefan M Pfister25,26,29, Richard J Gilbertson30, C David Allis9, Arul M Chinnaiyan1, Sophia Y Lunt4,31, Stefan Blüml2, Alexander R Judkins7, Sriram Venneti1,6.
Abstract
Childhood posterior fossa group A ependymomas (PFAs) have limited treatment options and bear dismal prognoses compared to group B ependymomas (PFBs). PFAs overexpress the oncohistone-like protein EZHIP (enhancer of Zeste homologs inhibitory protein), causing global reduction of repressive histone H3 lysine 27 trimethylation (H3K27me3), similar to the oncohistone H3K27M. Integrated metabolic analyses in patient-derived cells and tumors, single-cell RNA sequencing of tumors, and noninvasive metabolic imaging in patients demonstrated enhanced glycolysis and tricarboxylic acid (TCA) cycle metabolism in PFAs. Furthermore, high glycolytic gene expression in PFAs was associated with a poor outcome. PFAs demonstrated high EZHIP expression associated with poor prognosis and elevated activating mark histone H3 lysine 27 acetylation (H3K27ac). Genomic H3K27ac was enriched in PFAs at key glycolytic and TCA cycle–related genes including hexokinase-2 and pyruvate dehydrogenase. Similarly, mouse neuronal stem cells (NSCs) expressing wild-type EZHIP (EZHIP-WT) versus catalytically attenuated EZHIP-M406K demonstrated H3K27ac enrichment at hexokinase-2 and pyruvate dehydrogenase, accompanied by enhanced glycolysis and TCA cycle metabolism. AMPKα-2, a key component of the metabolic regulator AMP-activated protein kinase (AMPK), also showed H3K27ac enrichment in PFAs and EZHIP-WT NSCs. The AMPK activator metformin lowered EZHIP protein concentrations, increased H3K27me3, suppressed TCA cycle metabolism, and showed therapeutic efficacy in vitro and in vivo in patient-derived PFA xenografts in mice. Our data indicate that PFAs and EZHIP-WT–expressing NSCs are characterized by enhanced glycolysis and TCA cycle metabolism. Repurposing the antidiabetic drug metformin lowered pathogenic EZHIP, increased H3K27me3, and suppressed tumor growth, suggesting that targeting integrated metabolic/epigenetic pathways is a potential therapeutic strategy for treating childhood ependymomas.Entities:
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Year: 2021 PMID： 34613815 PMCID： PMC8762577 DOI： 10.1126/scitranslmed.abc0497
Source DB: PubMed Journal: Sci Transl Med ISSN： 1946-6234 Impact factor: 19.319