The discovery of high-frequency histone H3 missense mutations (‘oncohistones’) in pediatric gliomas was the first time that histone mutations were linked to any disease. Since the original discovery, monoallelic missense mutations in genes encoding histone H3 have been found in a variety of cancer types. Previous studies have led to mechanistic insights into how one class of oncohistones promotes tumorigenesis by demonstrating that lysine-to-methionine (K-to-M) substitutions transform histones from serving as substrates into specific and potent inhibitors of lysine methyltransferases.

Approximately 84% of diffuse intrinsic pontine glioma (DIPG) and 60% of high-grade non-brainstem pediatric midline gliomas contain a lysine 27-methionine (K27M) mutation. DIPG and other midline tumors have extremely low H3K27me3 levels caused by the action of the H3 K27M oncohistone. The H3 K27M protein binds to and inhibits the catalytic subunit (EZH2) of the Polycomb Repressive Complex 2 (PRC2), a conserved protein complex involved in gene silencing. Polycomb group (PcG) proteins are essential for development and are frequently misregulated in human cancers. Polycomb Repressive Complexes (PRC1, PRC2) function in a collaborative epigenetic cross-talk with H3K27me3 to initiate and maintain transcriptional silencing.

Posterior fossa type A (PFA) ependymomas also exhibit very low H3K27 methylation but lack the K27M oncohistone. Instead, PFA tumors express high levels of KIP75 (K27M-like inhibitor of PRC2, 75kDa, also termed CXORF67). We find that a highly conserved sequence within the C-terminus of KIP75 is necessary and sufficient to inhibit the catalytic activity of PRC2 in vitro and in vivo. Our biochemical experiments indicate that KIP75 directly interacts with the active site of the EZH2 subunit in a mechanism that is remarkably similar to the K27M oncohistone. Furthermore, expression of H3 K27M or KIP75 promote similar chromatin landscapes and gene expression profiles in cell culture. Our data indicate that PFA ependymoma and DIPG tumors are driven in part by the action of peptidyl PRC2 inhibitors that dysregulate gene silencing to promote tumorigenesis.

Citation Format: Peter W. Lewis. Aberrant polycomb repression in midline and hindbrain tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr SY44-02.