Inhibition of EZH2 or BET Suppresses Diffuse Intrinsic Pontine Glioma

Diffuse intrinsic pontine gliomas (DIPG) are aggressive pediatric brain tumors that are characterized by a histone H3 mutation (H3K27M) that is present in nearly 80% of cases. It has been proposed that H3K27M inhibits the polycomb repressive complex 2 (PRC2) by binding to the catalytic subunit EZH2, resulting in a global reduction of H3K27me3. However, residual PRC2 activity remains, and some genes retain H3K27me3. Thus, the role of H3K27M in tumor development is not completely understood. Mohammad and colleagues developed a mouse model of DIPG driven by H3K27M expression in neural stem cells expressing PDGFB. H3K27M promoted the development of tumors that resembled human DIPGs. Residual EZH2 activity was required for the growth of mouse DIPG cells in vitro and in vivo, and an EZH2 inhibitor reduced the growth of patient-derived DIPG cell lines. EZH2 inhibition induced senescence in the mouse and human cells via upregulation of p16^INK4A, which was normally repressed by H3K27M. Chromatin immunoprecipitation sequencing (ChIP-seq) indicated that despite the global reduction of H3K27me3 in H3K27M-expressing cells, strong polycomb target genes retained H3K27me3. A related study by Piunti and colleagues also demonstrated that PRC2 is required for the oncogenic proliferation of H3K27M-positive DIPG and that nucleosomes bearing H3K27M are also acetylated and recruit BRD4. ChIP-seq demonstrated that H3K27M localizes to H3K27ac sites and is excluded from PRC2 targets, suggesting that H3K27M-K27ac nucleosomes inhibit PRC2 and subsequently exclude PRC2 from chromatin regions bound by the H3K27M-K27ac. Further, H3K27M-K27ac nucleosomes colocalized with BET proteins at actively transcribed genes, and treatment with the BET inhibitor JQ1 reduced tumor growth and extended survival in a DIPG xenograft. Collectively, the results of these studies show that DIPGs depend on residual PRC2 activity and suggest that EZH2 or BET inhibitors may be beneficial in patients with H3K27M-expressing tumors.

Mohammad F, Weissmann S, Leblanc B, Pandey DP, Højfeldt JW, Comet I, et al. EZH2 is a potential therapeutic target for H3K27M-mutant pediatric gliomas. Nat Med 2017 Feb 27 [Epub ahead of print].

Piunti A, Hashizume R, Morgan MA, Bartom ET, Horbinski CM, Marshall SA, et al. Therapeutic targeting of polycomb and BET bromodomain proteins in diffuse intrinsic pontine gliomas. Nat Med 2017 Feb 27 [Epub ahead of print].