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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.

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Fig. 1: Localization and deposition pathways of histone variants across the genome.
Fig. 2: Histone variant mutational spectrum and altered expression across solid tumours.
Fig. 3: Histone variant hallmarks in tumorigenesis.

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Acknowledgements

The authors thank members of the Bernstein laboratory for discussions relevant to this Review. This work was supported by NIH/NCI grant R01CA154683, NIH/NCI grant R01CA218024, NIH/NINDS grant R01NS110837 (E.B.) and the American Skin Association Ping Y. Tai Foundation Research Grant in Skin Cancer/Melanoma (D.F.). The authors apologize to those whose work was not cited due to space constraints.

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D.F. and F.G.G. researched data for the article: All authors substantially contributed to discussion of the content, and wrote, reviewed and edited the manuscript before submission.

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Supplementary information

Glossary

Oncohistones

Missense mutations in a histone variant, most commonly H3.3, often altering a key post-translational modification site that leads to a tumorigenic gene expression programme driving specific malignancies in children or young adults.

YEATS domain

Histone post-translational modification reader module found in transcriptional regulator proteins that selectively binds to acetylated and crotonylated lysine residues.

Pericentric heterochromatin

Constitutively condensed chromatin localized adjacent to the centromere, formed on repetitive DNA satellite sequences repressed by DNA methylation and histone H3 lysine 9 trimethylation (H3K9me3).

Bivalent chromatin domains

Genomic regions that harbour both the repressive mark histone H3 lysine 27 trimethylation (H3K27me3) and the activating mark histone H3 lysine 4 trimethylation (H3K4me3) and poise a subset of genes silenced in embryonic stem cells for activation during subsequent cell fate decisions to drive normal development.

PRC2

Polycomb repressive complex 2 (PRC2) catalyses trimethylation of histone H3 lysine 27 to silence developmental genes during differentiation, and contributes to facultative heterochromatin formation at the inactive X chromosome and imprinted genes.

PRC1

Polycomb repressive complex 1 (PRC1) monoubiquitylates histone H2A lysine 119 to induce gene repression, in coordination with histone H3 lysine 27 trimethylation (H3K27me3) deposited by PRC2.

Poly(ADP-ribose) polymerase

An enzyme that attaches chains of ADP-ribose from an NAD+ donor molecule to acceptor proteins (including poly(ADP-ribose) polymerases themselves) to regulate DNA repair and carbohydrate and lipid metabolism.

Triple-negative breast cancer

Breast cancer subtype that does not express oestrogen and progesterone receptors or HER2, and therefore is not suited to hormone therapy or HER2 inhibition.

Euchromatin

The loosely compacted, transcriptionally active and gene-enriched fraction of chromatin.

Alternative lengthening of telomeres

(ALT). Telomerase-independent mechanism that exploits homologous recombination of repetitive telomere sequences to promote telomere length maintenance in certain immortalized cell lines and tumours.

Promyelocytic leukaemia bodies

Membraneless nuclear compartments formed on a scaffold of promyelocytic leukaemia protein involved in telomere lengthening and DNA damage response.

ADD domain

Protein domain consisting of an amino-terminal GATA-like zinc-finger, a plant homeodomain finger and a long carboxy-terminal α-helix which binds histone H3 unmethylated at lysine 4 and trimethylated at lysine 9.

SNF2 helicase domain

Protein domain that uses the energy of ATP hydrolysis to apply torsional strain to DNA in order to remodel nucleosomes and other DNA–protein complexes.

G-quadruplex structures

Stable secondary DNA structures present in G-rich DNA held together by G-G base pairs formed within the same DNA strand.

ATM

Ataxia telangiectasia mutated (ATM) is a DNA damage kinase that phosphorylates itself and downstream effectors in response to DNA double-strand breaks to coordinate the cellular DNA damage response.

Kinetochore

Multicomplex protein structure localized at the centromere during mitosis to attach, orient and move sister chromatids along the mitotic spindle, ensuring accurate chromosome segregation.

Neocentromeres

Abnormal centromeres formed de novo at a location distinct from the primary constriction of a chromosome.

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Ghiraldini, F.G., Filipescu, D. & Bernstein, E. Solid tumours hijack the histone variant network. Nat Rev Cancer 21, 257–275 (2021). https://doi.org/10.1038/s41568-020-00330-0

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