Histone H3K27M Mutation in Brain Tumors

Histones form chromatin and play a key role in the regulation of gene expression. As an epigenetic information form, histone modifications such as methylation, phosphorylation, acetylation, and ubiquitination are closely related to the regulation of genes. In the last two decades, cancer scientists discovered that some histone modifications, including acetylation and methylation, are perturbed in cancer diseases. Recurrent histone mutations, which hinder histone methylation and are implicated in oncogenesis, are recently identified in several cancer disease and called oncohistones. Well-known oncohistones, with mutations on both H3.1 and H3.3, include H3K36M in chondroblastoma, H3K27M in glioma, and H3G34 mutations that exist in bone cancers and gliomas. Oncohistone expression can lead to epigenome/transcriptome reprogramming and eventually to oncogenesis. The H3K27M, H3G34V/R, and H3K36M histone mutations can lead to the substitution of amino acid(s) at or near a lysine residue, which is a methylation target. H3K27M characteristically exists in diffuse intrinsic pontine glioma (pediatric DIPG), and its expression can cause a global decrease of the methylation of histone at the lysine residue. Uncovering the molecular mechanisms of H3K27M-driven tumorigenesis has recently led to the identification of some potential therapeutic targets in diffuse intrinsic pontine glioma. In this chapter, we will review and summarize recent studies on the H3K27M-driven tumorigenic mechanisms and properties and the role of H3.1K27M and H3.3K27M oncohistones in brain tumors.