Solid tumours hijack the histone variant network

Abstract

Cancer is a complex disease characterized by loss of cellular homeostasis through genetic and epigenetic alterations. Emerging evidence highlights a role for histone variants and their dedicated chaperones in cancer initiation and progression. Histone variants are involved in processes as diverse as maintenance of genome integrity, nuclear architecture and cell identity. On a molecular level, histone variants add a layer of complexity to the dynamic regulation of transcription, DNA replication and repair, and mitotic chromosome segregation. Because these functions are critical to ensure normal proliferation and maintenance of cellular fate, cancer cells are defined by their capacity to subvert them. Hijacking histone variants and their chaperones is emerging as a common means to disrupt homeostasis across a wide range of cancers, particularly solid tumours. Here we discuss histone variants and histone chaperones as tumour-promoting or tumour-suppressive players in the pathogenesis of cancer.

Fig. 1 |. Localization and deposition pathways of histone variants across the genome.

a | Histone variants are structurally similar to their canonical counterparts, with the exception of macroH2A’s non-histone macrodomain, which protrudes from the nucleosome particle via its linker region. Histone variants are differentially enriched across genomic landmarks as a function of histone chaperones. The CAF1 (chromatin assembly factor 1) complex deposits canonical H3 variants H3.1 and H3.2 during DNA replication or repair. H3.3 is deposited at active genes and at gene regulatory and nucleosome-depleted regions by the HIRA (histone cell cycle regulation-defective homologue A) complex, and at pericentric heterochromatin and subtelomeric regions by death domain-associated protein 6 (DAXX)–ATRX (α-thalassaemia/mental retardation syndrome X-linked). Centromeric protein A (CENP-A) is deposited at the active centromere by Holliday junction recognition protein (HJURP). NAP1 and the facilitates chromatin transcription (FACT) complex catalyse incorporation of canonical H2A during replication, and throughout the cell cycle, counterbalancing its continuous turnover (dashed lines). H2A.Z is deposited at active genes and regulatory regions by the SNF2-related CBP activator protein (SRCAP) and p400–TIP60 complexes, but is also enriched at pericentric heterochromatin through an unclear mechanism. The INO80 remodeling complex and ANP32E chaperone exchange H2A.Z for H2A at active genes, gene regulatory elements and DNA damage sites. APLF and FACT promote the accumulation of macroH2A1.1 and macroH2A1.2, respectively, at DNA damage sites. MacroH2A enrichment is negatively regulated by ATRX at telomeres and by FACT-mediated active eviction at transcribed genes. Crystal structures of canonical histones and H3.3 (REF.), CENP-A, H2A.Z, macroH2A–H2A heterotypic nucleosome and macroH2A macrodomain were rendered with use of EzMol. b | At gene-level resolution, H3.3 and H2A.Z are enriched at active regulatory elements (enhancers) and around the promoter of active genes, with the exception of the nucleosome-free region at the transcription start site (TSS). H3.3 is additionally present across transcribed gene bodies and transcription stop sites. MacroH2A forms large domains limited by actively transcribed regions.

Fig. 2 |. Histone variant mutational spectrum and altered expression across solid tumours.

a | From pan-cancer studies (The Cancer Genome Atlas cohorts used are listed in Supplementary Box 1), the mutational spectra of histone variant genes H2AFZ (encoding H2A.Z.1), H2AFV (encoding H2A.Z.2), H2AFY (encoding macroH2A1; both isoforms, macroH2A1.1 and macroH2A1.2, are included), H2AFY2 (encoding macroH2A2), H3F3A (encoding H3.3), H3F3B (encoding H3.3) and CENPA are shown. Most histone variants show a low frequency of mutation. H3F3A has hotspot mutations (denoted by flame symbol) that represent K27M/R and G34R/V mutations. While in adult cancers these mutations are diluted, cohorts of paediatric tumours (blue axis; right) have higher mutation frequency in these hotspots. Histones are not drawn to scale. Green dots represent missense somatic mutations, while black dots indicate truncations. b | Histone variant alterations across the human body by location; H2A.Z, centromeric protein A (CENP-A) and macroH2A display altered regulation in diverse adult cancers, while H3.3 alterations are restricted to paediatric tumours. aa, amino acids.

Fig. 3 |. Histone variant hallmarks in tumorigenesis.

a | The role of altered histone variants in tumorigenesis can be categorized into eight major hallmarks as shown. MacroH2A is associated with the highest number of hallmarks, underlying its highly versatile role in tumour development. Centromeric protein A (CENP-A) contributes to replicative immortality via its function in chromosome segregation. H3.3 alteration affects pathways involving replicative immortality due to its role in telomere maintenance, senescence, increased proliferation and loss of cell identity. Lastly, H2A.Z alterations affect mainly proliferation-associated pathways. b | Contribution of altered histone variants and their chaperones to the stages of tumour development. A large number of studies have addressed the impact of altered histone variants on proliferation, as shown in the ‘tumour growth’ phase. Although H3.3K27M cannot initiate transformation on its own, this mutation occurs very early during tumorigenesis. Few reports have linked histone variants to invasion or metastasis mechanistically; however, there is evidence that macroH2A may reduce tumour invasiveness and metastatic potential, while deposition of H3.3 in favour of H3.1 sustains induction of genes that promote epithelial–mesenchymal transition. ATRX, α-thalassaemia/mental retardation syndrome X-linked; DAXX, death domain-associated protein 6, HJURP, Holliday junction recognition protein.