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
Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.
Nat Med. 2014 Dec;20(12):1394-6. doi: 10.1038/nm.3716. Epub 2014 Nov 17.
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.
小儿脑干胶质瘤通常携带致癌性组蛋白H3.3的K27M突变。在此我们表明，GSKJ4对K27去甲基化酶JMJD3的药理抑制作用可增加K27M肿瘤细胞中的细胞H3K27甲基化，并在体外对K27M细胞以及在体内对K27M异种移植瘤均显示出强大的抗肿瘤活性。我们的结果表明，通过抑制K27去甲基化酶来增加H3K27甲基化是治疗表达K27M的脑干胶质瘤的一种有效治疗策略。
