Oncohistones: drivers of pediatric cancers

Abstract

One of the most striking results in the area of chromatin and cancer in recent years has been the identification of recurrent mutations in histone genes in pediatric cancers. These mutations occur at high frequency and lead to the expression of mutant histones that exhibit oncogenic features. Thus, they are termed oncohistones. Thus far, mutations have been found in the genes encoding histone H3 and its variants. The expression of the oncohistones affects the global chromatin landscape through mechanisms that have just begun to be unraveled. In this review, we provide an overview of histone mutations that have been identified and discuss the possible mechanisms by which they contribute to tumor development. We further discuss the targeted therapies that have been proposed to treat cancers expressing oncohistones.

Keywords: cancer; chromatin; oncohistone.

Figure 1.

Nucleosomes, expression of H3 proteins, and their incorporation into nucleosomes. (A) Schematic diagram showing a nucleosome, which consists of a histone octamer (containing two copies each of H2A, H2B, H3, and H4) and 146 base pairs of DNA wrapped around the octamer. (B) Expression of canonical (H3.1 and H3.2) and variant (H3.3) histone H3 during the cell cycle. H3.1 and H3.2 are expressed only during the S phase of the cell cycle, and their incorporation into the chromatin is coupled with DNA replication, whereas H3.3 is expressed and incorporated throughout the cell cycle independently of DNA replication. (C) Sequence alignment of H3.1, H3.2, and H3.3 proteins. Residues that are not conserved are shown in red, and the residues that are found to be mutated in tumors are highlighted. (D) Differential incorporation of canonical and variant H3 into chromatin. During S phase, H3.1 and H3.2 are deposited into chromatin throughout the chromosome by CAF1 (chromatin-associated factor 1), while H3.3 is incorporated at distinct genomic loci by two dedicated histone chaperons. The ATRX/DAXX complex mediates the assembly of H3.3 at telomeres and pericentric heterochromatin, while HIRA mediates the incorporation of H3.3 at euchromatic regions, including promoters, gene bodies, and regulatory elements.

Figure 2.

Different mutations in histone H3 are found in tumors located in distinct anatomical locations. Depicted here is the occurrence of G34R/V and K27M mutations in different anatomical regions in the brain. G34R/V mutants are restricted to the tumors located in cerebral cortex, while the K27M mutant is found only in tumors of the midline structure (including the thalamus, cerebellum, brain stem, spine, and fourth ventricle).

Figure 3.

Proposed mechanisms by which oncohistones affect the activity of histone methyltransferases (HMTs). (A) K-to-M mutant histones bind more tightly to the catalytic site within the SET domain of HMTs than wild-type histones, leading to sequestration of the HMT complex to mutant nucleosomes and rendering the HMT nonproductive due to the absence of the substrate. (B) The G34 residue of histone H3 is buried in a narrow tunnel within the active site of SETD2. Mutation of G34 to residues with a larger side chain (R/V/W/L) might result in distortion of the catalytic site that would render SETD2 inactive.