Oncohistones: a roadmap to stalled development

Abstract

Since the discovery of recurrent mutations in histone H3 variants in pediatric brain tumours, so-called 'oncohistones' have been identified in various cancers. While their mechanism of action remains under active investigation, several studies have shed light on how they promote genome-wide epigenetic perturbations. These findings converge on altered post-translational modifications on two key lysine (K) residues of the H3 tail, K27 and K36, which regulate several cellular processes, including those linked to cell differentiation during development. We will review how these oncohistones affect the methylation of cognate residues, but also disrupt the distribution of opposing chromatin marks, creating genome-wide epigenetic changes which participate in the oncogenic process. Ultimately, tumorigenesis is promoted through the maintenance of a progenitor state at the expense of differentiation in defined cellular and developmental contexts. As these epigenetic disruptions are reversible, improved understanding of oncohistone pathogenicity can result in needed alternative therapies. Accepted ArticleThis article is protected by copyright. All rights reserved A number of cancers carry recurrent, somatic, gain-of-function, heterozygous mutations in different histone 3 (H3)-encoding genes, which lead to amino acid substitutions on key residues of the H3 tail. These hotspot H3 mutations, oncohistones as we label them, were first identified in a deadly brain cancer, pediatric high-grade gliomas (pHGGs), where they account for a large proportion of these tumours. Notably, they show remarkable spatio-temporal specificity, indicating that their pathogenesis may be closely linked to aberrant development [1,2]. Indeed, HGGs of the central nervous system midline (which includes the pons, thalamus and spine) target younger children, and show a high frequency (~80%) of H3 lysine to methionine, or rarely to isoleucine, substitutions (K27M/I). These K27M/I mutations occur in either canonical H3.1/H3.2 variants mainly in the pons, or in the non-canonical H3.3 variant across all brain midline structures (Figure 1) [2][3][4][5][6]. By contrast, in HGGs of the brain hemispheres, glycine 34 to arginine or valine (G34R/V) substitutions are specific to H3F3A, which encodes the H3.3 variant, and target primarily the temporo-parietal cortex in adolescents and young adults, where they account for ~30% of these tumours [2][3][4][5][6]. Other hemispheric H3 wild-type gliomas of adolescents and young adults (mean age of 33 years) occur primarily in fronto-parietal lobes and carry non-overlapping truncating mutations in SETD2 [7], the only H3K36 tri-methyltransferase in humans, and/or hotspot somatic mutations in isocitrate dehydrogenases 1/2 (IDH1/2) [3,6,[8][9][10]. IDH mutations generate a neomorphic enzyme and excess production of the oncometabolite 2-hydroxyglutarate, which competitively inhibits histone and DNA demethylases to affect the methylation of K residues on the H3 tail and promote a CpG island methylator phenotype (CIMP). Together, ...

Set2 histone methyltransferase regulates transcription coupled-nucleotide excision repair in yeast

“…Because histone H3K36 methylation is frequently dysregulated in human cancers, these findings have important implications for carcinogenesis. Set2 homologs, including NSD1, NSD2, NSD3, and SETD2, are frequently mutated, translocated, or amplified in a variety of human cancers [51,52], and oncohistone mutations that dysregulate H3K36 methylation cause pediatric brain tumors [67]. Moreover, amplifications or mutations in Set2 homologs in human cancers has been linked to chemotherapy resistance [68][69][70], including to chemotherapeutics that cause DNA lesions repaired by NER (e.g., cisplatin and melphalan).…”

Aberrant DNA repair is a vulnerability in histone H3.3-mutant brain tumors

“…H3.3 K27M and G34R affect RF repair through a mechanism that is distinct from their interference with gene expression programs (Deshmukh et al, 2021; Haase et al, 2022; Phillips et al, 2020). The aberrant use of NHEJ in S phase indeed does not rely on H3K27me3 and H3K36me3 alterations, but may involve other PTM changes in mutant nucleosomes, possibly through the activity of histone modifying enzymes, which may in turn affect the binding of repair factors.…”

“…For protein identification, Thermo .RAW files were converted to the .mzXML format using Proteowizard (Kessner et al, 2008), then searched using X!Tandem (Craig and Beavis, 2004) and COMET (Eng et al, 2013) against the human Human RefSeq Version 45 database (containing 36,113 entries). Data were analyzed using the trans-proteomic pipeline (TPP) (Deutsch et al, 2010;Pedrioli, 2010) via the ProHits software suite (v3.3) (Liu et al, 2010).…”

“…One such feature is exemplified by heterozygous, dominant point mutations in the H3F3A gene, which encodes the H3.3 histone variant. These recurrent mutations are active players in the oncogenic process in pHGG (Deshmukh et al, 2021), with three mutually exclusive mutations resulting in single amino-acid substitutions at Lysine 27 to Methionine (H3.3K27M), giving rise to midline tumors of the central nervous system, or at Glycine 34 to Arginine or Valine (H3.3G34R/V) in cerebrocortical tumors (Schwartzentruber et al, 2012; Sturm et al, 2012; Wu et al, 2012). These mutations perturb histone post-translational modifications (PTMs) in cis (Fang et al, 2018; Shi et al, 2018) or in trans (Fang et al, 2016; Lewis et al, 2013), thus interfering with genome-wide gene expression programs, stalling the differentiation of interneuron progenitor cells at different stages (Bjerke et al, 2013; Chen et al, 2020a; Filbin et al, 2018; Jessa et al, 2019) and fueling cell transformation (reviewed in (Deshmukh et al, 2021; Phillips et al, 2020; Sahu and Lu, 2022)).…”

Oncohistones: Exposing the nuances and vulnerabilities of epigenetic regulation

“…However, such reasoning was challenged about a decade ago following the discovery of somatic missense mutations in histone H3 genes that occur with high genetic penetrance in rare pediatric brain and bone cancers (Schwartzentruber et al, 2012;Wu et al, 2012;Behjati et al, 2013). These findings mobilized the epigenetics community to investigate if and how these mutants might alter cellular phenotypes (Deshmukh et al, 2022;Sahu and Lu, 2022). Thanks to the efforts of many laboratories, we now know that certain N-terminal histone H3 mutations function as cancer drivers (Hoffman et al, 2016;Nikbakht et al, 2016;Lu et al, 2016;Larson et al, 2019;Silveira et al, 2019;Harutyunyan et al, 2019;Khazaei et al, 2020).…”