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

被引：372

作者：

Hashizume, Rintaro ^{[1
]}

Andor, Noemi ^{[2
]}

Ihara, Yuichiro ^{[2
]}

Lerner, Robin ^{[2
]}

Gan, Haiyun ^{[3
]}

Chen, Xiaoyue ^{[3
]}

Fang, Dong ^{[3
]}

Huang, Xi ^{[4
]}

Tom, Maxwell W. ^{[2
]}

Ngo, Vy ^{[5
]}

Solomon, David ^{[6
,7
]}

Mueller, Sabine ^{[2
,8
,9
]}

Paris, Pamela L. ^{[5
]}

Zhang, Zhiguo ^{[3
]}

Petritsch, Claudia ^{[2
]}

Gupta, Nalin ^{[2
]}

Waldman, Todd A. ^{[7
]}

James, C. David ^{[1
]}

机构：

[1] Northwestern Univ, Dept Neurol Surg, Feinberg Sch Med, Chicago, IL 60611 USA

[2] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA USA

[3] Mayo Clin, Dept Biochem & Mol Biol, Rochester, MN USA

[4] Univ Calif San Francisco, Dept Physiol, San Francisco, CA USA

[5] Univ Calif San Francisco, Dept Urol, San Francisco, CA USA

[6] Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94140 USA

[7] Georgetown Univ, Sch Med, Lombardi Comprehens Canc Ctr, Washington, DC USA

[8] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA

[9] Univ Calif San Francisco, Dept Pediat, San Francisco, CA USA

来源：

NATURE MEDICINE | 2014年 / 20卷 / 12期

基金：

美国国家卫生研究院;

关键词：

HIGH-GRADE GLIOMAS; GENE-EXPRESSION; GLIOBLASTOMA; METHYLATION; MUTATIONS; H3K27ME3; EZH2;

D O I：

10.1038/nm.3716

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：1394 / 1396

页数：3

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