Histone H3 mutations—a special role for H3.3 in tumorigenesis?

Abstract

Brain tumors are the most common solid tumors in children. Pediatric high-grade glioma (HGG) accounts for ∼8–12 % of these brain tumors and is a devastating disease as 70–90 % of patients die within 2 years of diagnosis. The failure to advance therapy for these children over the last 30 years is largely due to limited knowledge of the molecular basis for these tumors and a lack of disease models. Recently, sequencing of tumor cells revealed that histone H3 is frequently mutated in pediatric HGG, with up to 78 % of diffuse intrinsic pontine gliomas (DIPGs) carrying K27M and 36 % of non-brainstem gliomas carrying either K27M or G34R/V mutations. Although mutations in many chromatin modifiers have been identified in cancer, this was the first demonstration that histone mutations may be drivers of disease. Subsequent studies have identified high-frequency mutation of histone H3 to K36M in chondroblastomas and to G34W/L in giant cell tumors of bone, which are diseases of adolescents and young adults. Interestingly, the G34 mutations, the K36M mutations, and the majority of K27M mutations occur in genes encoding the replacement histone H3.3. Here, we review the peculiar characteristics of histone H3.3 and use this information as a backdrop to highlight current thinking about how the identified mutations may contribute to disease development.

The role of histone modifications and telomere alterations in the pathogenesis of diffuse gliomas in adults and children

“…H3.3 varies from H3.1 by five amino acids (codons 31, 87, 89, 90, and 96) with amino acid 31 being a serine of the H3.3 N-terminal tail that can be phosphorylated [5]. The incorporation of H3.3 into telomeric and pericentric chromatin is accomplished by ATRX-DAXX (alpha thalassemia/mental retardation syndrome X-linked and death-domain associated protein) chaperone protein complex, while HIRA (histone regulator A) deposits H3.3 into chromatin areas of active and suppressed genes [6, 7, 8, 9]. …”

“…However mutations directly affecting histone genes were originally described in gliomas [1, 28, 29, 30], and have been subsequently found in chondroblastomas and giant cell tumors of bone [6, 31]. Tail mutations of histone H3 at amino acids 27 and 34 leading to K27M (lysine to methionine substitution at codon 27) and G34R/V (glycine to arginine or valine substitution at codon 34) were initially reported in 36% of non-brainstem pediatric high-grade gliomas, with 14% containing G34R/V mutations and 22% containing K27M mutations [29] (Table 1).…”

“…As glycine is a small uncharged amino acid residue, substitution with arginine or valine likely alters the post-translational modifications that occur at lysine 36 through steric inhibition or conformational tail changes, thereby interfering with code writers, erasers, and readers [1, 6]. Decreased histone H3 K36 trimethylation (H3K36me3) is observed within nucleosomes that contain an H3.3 G34R/V mutated tail.…”

Multifaceted role of the polycomb-group gene EZH2 in hematological malignancies

“…H3K27 M mutation likely stabilizes the binding of PRC2 to H3K27 M, thereby preventing deposition of methyl marks on other H3. Total H3K27me2/3 levels are thus profoundly reduced in cells expressing the K27M mutant allele, resulting in mis-regulation of PRC2 target genes [24]. All these findings indicate the tumor suppressive role of EZH2-PRC2 in a subset of solid tumors.…”

Oncogenic Mechanisms of Histone H3 Mutations

“…Recurrent histone mutations in human cancer (see text and Fontebasso et al 2014a; Kallappagoudar et al 2015). pHGG, Pediatric high-grade glioma; GCT, giant cell tumor.…”