Pharmacologic inhibition of histone demethylation as a therapy for pediatric brainstem glioma

• Published in: Nature medicine Vol. 20; no. 12; pp. 1394 - 1396
• Main Authors: Hashizume, Rintaro, Andor, Noemi, Ihara, Yuichiro, Lerner, Robin, Gan, Haiyun, Chen, Xiaoyue, Fang, Dong, Huang, Xi, Tom, Maxwell W, Ngo, Vy, Solomon, David, Mueller, Sabine, Paris, Pamela L, Zhang, Zhiguo, Petritsch, Claudia, Gupta, Nalin, Waldman, Todd A, James, C David
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.12.2014
• Subjects: Animals; Apoptosis - drug effects; Benzazepines - pharmacology; Brain cancer; Brain Stem Neoplasms - genetics; Brain Stem Neoplasms - metabolism; Cell growth; Cell Line, Tumor; Cell Proliferation - drug effects; Child; Drug therapy; Gene Expression Regulation, Neoplastic; Genetic aspects; Glioma - genetics; Glioma - metabolism; Gliomas; Histones; Histones - drug effects; Histones - genetics; Histones - metabolism; Humans; Jumonji Domain-Containing Histone Demethylases - antagonists & inhibitors; Jumonji Domain-Containing Histone Demethylases - metabolism; Methylation; Methylation - drug effects; Mice; Mutation; Pediatrics; Pharmacology; Physiological aspects; Pyrimidines - pharmacology; Tumors; Xenograft Model Antitumor Assays; United States
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm.3716

Pediatric brainstem gliomas often harbor oncogenic K27M mutation of histone H3.3. Here we show that GSKJ4 pharmacologic inhibition of K27 demethylase JMJD3 increases cellular H3K27 methylation in K27M tumor cells and demonstrate potent antitumor activity both in vitro against K27M cells and in vivo against K27M xenografts. Our results demonstrate that increasing H3K27 methylation by inhibiting K27 demethylase is a valid therapeutic strategy for treating K27M-expressing brainstem glioma.