Targeting integrated epigenetic and metabolic pathways in lethal childhood PFA ependymomas.

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.

• Authors: Pooja Panwalkar, Benita Tamrazi, Derek Dang, Chan Chung, Stefan Sweha, Siva Kumar Natarajan, Matthew Pun, Jill Bayliss, Martin P Ogrodzinski, Drew Pratt, Brendan Mullan, Debra Hawes, Fusheng Yang, Chao Lu, Benjamin R Sabari, Abhinav Achreja, Jin Heon, Olamide Animasahun, Marcin Cieslik, Christopher Dunham, Stephen Yip, Juliette Hukin, Joanna J Phillips, Miriam Bornhorst, Andrea M Griesinger, Andrew M Donson, Nicholas K Foreman, Hugh J L Garton, Jason Heth, Karin Muraszko, Javad Nazarian, Carl Koschmann, Li Jiang, Mariella G Filbin, Deepak Nagrath, Marcel Kool, Andrey Korshunov, Stefan M Pfister, Richard J Gilbertson, C David Allis, Arul M Chinnaiyan, Sophia Y Lunt, Stefan Blüml, Alexander R Judkins, Sriram Venneti
• Journal: Science translational medicine (Sci Transl Med) Vol. 13 Issue 614 Pg. eabc0497 (Oct 06 2021) ISSN: 1946-6242 [Electronic] United States
• PMID: 34613815 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Histones

Topics

• Animals
• Child
• Ependymoma (genetics)
• Epigenesis, Genetic
• Epigenomics
• Histones (genetics)
• Humans
• Metabolic Networks and Pathways
• Mice