Histone H3 Mutations in Cancer

Yi Ching Esther Wan, Jiaxian Liu, Kui Ming Chan

Histone modifications are one form of epigenetic information that relate closely to gene regulation. Aberrant histone methylation caused by alteration in chromatin-modifying enzymes has long been implicated in cancers. More recently, recurrent histone mutations have been identified in multiple cancers and have been shown to impede histone methylation. All three histone mutations (H3K27M, H3K36M, and H3G34V/R) identified result in amino acid substitution at/near a lysine residue that is a target of methylation. In the cases of H3K27M and H3K36M, found in pediatric DIPG (diffuse intrinsic pontine glioma) and chondroblastoma respectively, expression of the mutant histone leads to global reduction of histone methylation at the respective lysine residue. These mutant histones are termed "oncohistones" because their expression reprograms the epigenome and shapes an oncogenic transcriptome. Dissecting the mechanism of H3K27M-driven oncogenesis has led to the discovery of promising therapeutic targets in pediatric DIPG. The purpose of this review is to summarize the work done on identifying and dissecting the oncogenic properties of histone H3 mutations.