Targeting integrated epigenetic and metabolic pathways in lethal childhood PFA ependymomas

Pooja Panwalkar(University of Michigan), Benita Tamrazi(Children's Hospital of Los Angeles), Derek Dang(University of Michigan), Chan Chung(Daegu Gyeongbuk Institute of Science and Technology), Stefan R. Sweha(University of Michigan), Siva Kumar Natarajan(University of Michigan), Matthew Pun(University of Michigan), Jill Bayliss(University of Michigan), Martin P. Ogrodzinski(Michigan State University), Drew Pratt(University of Michigan), Brendan Mullan(University of Michigan), Debra Hawes(Children's Hospital of Los Angeles), Fusheng Yang(Children's Hospital of Los Angeles), Chao Lü(Columbia University Irving Medical Center), Benjamin R. Sabari(Rockefeller University), Abhinav Achreja(University of Michigan), Jin Heon(University of Michigan), Olamide Animasahun(University of Michigan), Marcin Cieślik(University of Michigan), Christopher Dunham(University of British Columbia), Stephen Yip(University of British Columbia), Juliette Hukin(Children's & Women's Health Centre of British Columbia), Joanna J. Phillips(University of California, San Francisco), Miriam Bornhorst(Children's National), Andrea M. Griesinger(Morgan Adams Foundation), Andrew M. Donson(Morgan Adams Foundation), Nicholas K. Foreman(University of Michigan), Hugh Garton(University of Michigan), Jason Heth(University of Michigan), Karin M. Muraszko(University of Michigan), Javad Nazarian(Children's National), Carl Koschmann(University of Michigan), Li Jiang(Dana-Farber/Boston Children's Cancer and Blood Disorders Center), Mariella G. Filbin(Dana-Farber/Boston Children's Cancer and Blood Disorders Center), Deepak Nagrath(University of Michigan), Marcel Kool(German Cancer Research Center), Andrey Korshunov(German Cancer Research Center), Stefan M. Pfister(German Cancer Research Center), Richard J. Gilbertson(Cancer Research UK), C. David Allis(Rockefeller University), Arul M. Chinnaiyan(University of Michigan), Sophia Y. Lunt(Michigan State University), Stefan Blüml(Children's Hospital of Los Angeles), Alexander R. Judkins(Children's Hospital of Los Angeles), Sriram Venneti(University of Michigan)
Science Translational Medicine
October 6, 2021
10.1126/scitranslmed.abc0497
Cited by 59Open Access
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Abstract

, 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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