The H3K27 demethylase inhibitor GSKJ4 suppresses H3.3 K27M–mutant pediatric brainstem glioma growth.

  • Major finding: The H3K27 demethylase inhibitor GSKJ4 suppresses H3.3 K27M–mutant pediatric brainstem glioma growth.

  • Mechanism: GSKJ4 increases cellular H3K27 methylation and alters gene expression via inhibition of JMJD3.

  • Impact: Modulation of H3K27 methylation is a potential therapeutic strategy for K27M-mutant pediatric gliomas.

Mutations in the histone variant H3.3 are common in pediatric brainstem gliomas, with substitution of lysine 27 with methionine (K27M) being the most common. This oncogenic mutation results in the loss of a critical posttranslational methylation site, leading to decreased cellular H3K27 methylation and altered gene expression that contributes to tumorigenesis. Hashizume and colleagues hypothesized that suppression of H3K27 demethylation via treatment with GSKJ4, a pharmacologic inhibitor of the K27 demethylase lysine (K)-specific demethylase 6B (KDM6B, also known as JMJD3) would reduce the growth of K27M-mutant brainstem gliomas. Consistent with this idea, GSKJ4 treatment increased K27 dimethylation and trimethylation in K27M-mutant glioma cells in a dose- and time-dependent manner. GSKJ4 specifically inhibited the growth of cell lines expressing K27M-mutant H3.3, but not those expressing wild-type or G34V-mutant H3.3. The antitumor effect of GSKJ4 treatment was mediated by inhibition of JMJD3, as depletion of JMJD3, but not lysine (K)-specific demethylase 6A (KDM6A, also known as UTX), inhibited the growth of K27M-expressing cells, similar to the effects of GSKJ4 treatment. Furthermore, in vivo treatment with GSKJ4 suppressed the growth of both subcutaneous and orthotopic K27M-mutant brainstem glioma xenografts and prolonged the survival of tumor-bearing mice, whereas mice harboring wild-type H3.3 xenografts showed no response to GSKJ4. Importantly, analysis of isolated brain tissue confirmed that GSKJ4 entered the brain and was detected within the brainstem. These results demonstrate the antitumor activity of GSKJ4 and support additional testing of H3K27 demethylation inhibitors as a therapeutic strategy to treat K27M-mutant pediatric brainstem gliomas.

Hashizume R, Andor N, Ihara Y, Lerner R, Gan H, Chen X, et al. Pharmacologic inhibition of histone demethylation as a therapy for pediatric brainstem glioma. Nat Med 2014 Nov 17 [Epub ahead of print].