-
Views
-
Cite
Cite
Noemi Ander, Robin Lerner, Xi Huang, Maxwell Tom, Vy Ngo, David Solomon, Sabine Mueller, Pamela Paris, Zhiguo Zhang, Nalin Gupta, Todd Waldman, Stewart Goldman, David James, Rintaro Hashizume, BT-03
TARGETED INHBITION OF HISTONE DEMETHYLASE ACTIVITY FOR THE TREATMENT OF PEDIATRIC BRAINSTEM GLIOMAS, Neuro-Oncology, Volume 17, Issue suppl_3, June 2015, Page iii4, https://doi.org/10.1093/neuonc/nov061.13Close - Share Icon Share
Extract
INTRODUCTION: Histone gene mutations occur in pediatric brainstem gliomas. The most common mutation, a substitution of methionine for lysine at position 27 (K27M) of H3.3 protein, one of the histone H3 family members, causes substantial reduction in histone H3 tri- and di-methylation of K27 in cellular chromatin. We hypothesize that increase histone methylation would be a unique epigenetic therapeutic approach for treating this cancer. METHODS: Histone H3.3 lysine 27 (H3K27) methylation status was evaluated by western blotting. Cell proliferation assays were performed to assess the response to pharmacological inhibition with GSKJ4, a selective inhibitor of H3K27 demethylase JMJD3 and genetic suppression using JMJD3 siRNA. Gene expression changes and sequence association of K27me3, as a result of GSKJ4 treatment, were examined in cells with the K27M mutation using CHIP sequence and gene expression array. In vivo tumor growth and response to therapy were quantitatively measured by bioluminescence imaging and animal survival. RESULTS: H3.3K27M mutant brainstem glioma cells showed global reduction of H3K27 methylation compared to H3.3 wild-type glioma cells. Pharmacologic inhibition and genetic suppression of the H3K27 demethylase JMJD3, had anti-tumor activities that are specific to glioma cells with K27M mutation. Inhibition of JMJD3 opposed the suppressive effect of K27M mutation on H3K27 tri- and di-methylation. GSKJ4 treatment reduced the growth rate of K27M brainstem glioma xenografts in mice, while promoted tumor cell death, and significantly extended animal survival. Gene expression array combined with CHIP sequence association of K27me3, as result of GSKJ4 treatment, revealed 25 genes for which there was a strong correlation between GSKJ4-associated gene expression changes and corresponding changes in K27me3 sequence association. CONCLUSIONS: Our findings suggest that pharmacologic modulation of histone K27 methylation by inhibiting the JMJD3 demethylase is a viable approach for treating with pediatric gliomas with H3F3A mutations.
