한빛사논문
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,*
1Laboratory of Brain Tumor Metabolism and Epigenetics, Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA. 2Department of Radiology, Children’s Hospital Los Angeles, Keck School of Medicine University of Southern California, Los Angeles, CA 90027, USA. 3Department of New Biology, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu 42988, Korea. 4Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824, USA. 5Department of Physiology, Michigan State University, East Lansing, MI 48824, USA. 6Department of Pediatrics, Michigan Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA. 7Department of Pathology and Laboratory Medicine, Children’s Hospital Los Angeles, Keck School of Medicine University of Southern California, Los Angeles, CA 90027, USA. 8Department of Genetics and Development and Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA. 9Laboratory of Chromatin Biology and Epigenetics, Rockefeller University, New York, NY 10065, USA. 10Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA. 11Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109, USA. 12Department of Chemical Engineering, University of Michigan, Ann Arbor, MI 48109, USA. 13Division of Anatomic Pathology, British Columbia Children's Hospital, Vancouver, British Columbia V6H 3N1, Canada. 14Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada. 15Division of Hematology and Oncology, Children's and Women's Health Centre of B.C., University of British Columbia, Vancouver, British Columbia V6H 3N1, Canada. 16Department of Pathology, University of California San Francisco, San Francisco, CA 94132, USA. 17Department of Neurological Surgery, University of California San Francisco, San Francisco, CA 94132, USA. 18Research Center for Genetic Medicine, Children's National Health System, Washington, DC 20012, USA. 19Brain Tumor Institute, Children's National Health System, Washington, DC 20012, USA. 20Department of Pediatrics, University of Colorado, Denver, Aurora, CO 80045, USA. 21Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children's Hospital Colorado, Aurora, CO 80045, USA. 22Department of Neurosurgery, University of Michigan, Ann Arbor, MI 48109, USA. 23DMG Research Center, Department of Oncology, University Children's Hospital, CH-8032 Zürich, Switzerland. 24Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, MA 02115, USA. 25Hopp Children’s Cancer Center (KiTZ), Heidelberg 69120, Germany. 26Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg 69120, Germany. 27Princess Máxima Center for Pediatric Oncology, Utrecht 3584, Netherlands. 28Depart-ment of Neuropathology, German Cancer Research Center (DKFZ), University Hospital Heidelberg and CCU Neuropathology, Heidelberg 69120, Germany. 29Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg 69120, Germany. 30Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge CB2 0RE, UK. 31Department of Chemical Engineering and Materials Science, Michigan State University, East Lansing, MI 48824, USA.
*Corresponding author.
†These authors contributed equally to this work.
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.
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