A mutation in histone H2B represents a new class of oncogenic driver

Richard L. Bennett, Aditya Bele, Eliza C. Small, Christine M. Will, Behnam Nabet, Jon A. Oyer, Xiaoxiao Huang, Rajarshi P. Ghosh, Adrian T. Grzybowski, Tao Yu, Qiao Zhang, Alberto Riva, Tanmay P. Lele, George C. Schatz, Neil L. Kelleher, Alexander J. Ruthenburg, Jan Liphardt, Jonathan D. Licht

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

By examination of the cancer genomics database, we identified a new set of mutations in core histones that frequently recur in cancer patient samples and are predicted to disrupt nucleosome stability. In support of this idea, we characterized a glutamate to lysine mutation of histone H2B at amino acid 76 (H2B-E76K), found particularly in bladder and head and neck cancers, that disrupts the interaction between H2B and H4. Although H2B-E76K forms dimers with H2A, it does not form stable histone octamers with H3 and H4 in vitro, and when reconstituted with DNA forms unstable nucleosomes with increased sensitivity to nuclease. Expression of the equivalent H2B mutant in yeast restricted growth at high temperature and led to defective nucleosome-mediated gene repression. Significantly, H2B-E76K expression in the normal mammary epithelial cell line MCF10A increased cellular proliferation, cooperated with mutant PIK3CA to promote colony formation, and caused a significant drift in gene expression and fundamental changes in chromatin accessibility, particularly at gene regulatory elements. Taken together, these data demonstrate that mutations in the globular domains of core histones may give rise to an oncogenic program due to nucleosome dysfunction and deregulation of gene expression. SIGNIFICANCE: Mutations in the core histones frequently occur in cancer and represent a new mechanism of epigenetic dysfunction that involves destabilization of the nucleosome, deregulation of chromatin accessibility, and alteration of gene expression to drive cellular transformation.

Original languageEnglish
Pages (from-to)1438-1451
Number of pages14
JournalCancer Discovery
Volume9
Issue number10
DOIs
Publication statusPublished - Oct 2019

Fingerprint

Nucleosomes
Histones
Mutation
Gene Expression
Chromatin
Neoplasms
Regulator Genes
Head and Neck Neoplasms
Genomics
Urinary Bladder Neoplasms
Epigenomics
Lysine
Glutamic Acid
Breast
Yeasts
Epithelial Cells
Cell Proliferation
Databases
Amino Acids
Cell Line

ASJC Scopus subject areas

  • Oncology

Cite this

Bennett, R. L., Bele, A., Small, E. C., Will, C. M., Nabet, B., Oyer, J. A., ... Licht, J. D. (2019). A mutation in histone H2B represents a new class of oncogenic driver. Cancer Discovery, 9(10), 1438-1451. https://doi.org/10.1158/2159-8290.CD-19-0393

A mutation in histone H2B represents a new class of oncogenic driver. / Bennett, Richard L.; Bele, Aditya; Small, Eliza C.; Will, Christine M.; Nabet, Behnam; Oyer, Jon A.; Huang, Xiaoxiao; Ghosh, Rajarshi P.; Grzybowski, Adrian T.; Yu, Tao; Zhang, Qiao; Riva, Alberto; Lele, Tanmay P.; Schatz, George C.; Kelleher, Neil L.; Ruthenburg, Alexander J.; Liphardt, Jan; Licht, Jonathan D.

In: Cancer Discovery, Vol. 9, No. 10, 10.2019, p. 1438-1451.

Research output: Contribution to journalArticle

Bennett, RL, Bele, A, Small, EC, Will, CM, Nabet, B, Oyer, JA, Huang, X, Ghosh, RP, Grzybowski, AT, Yu, T, Zhang, Q, Riva, A, Lele, TP, Schatz, GC, Kelleher, NL, Ruthenburg, AJ, Liphardt, J & Licht, JD 2019, 'A mutation in histone H2B represents a new class of oncogenic driver', Cancer Discovery, vol. 9, no. 10, pp. 1438-1451. https://doi.org/10.1158/2159-8290.CD-19-0393
Bennett RL, Bele A, Small EC, Will CM, Nabet B, Oyer JA et al. A mutation in histone H2B represents a new class of oncogenic driver. Cancer Discovery. 2019 Oct;9(10):1438-1451. https://doi.org/10.1158/2159-8290.CD-19-0393
Bennett, Richard L. ; Bele, Aditya ; Small, Eliza C. ; Will, Christine M. ; Nabet, Behnam ; Oyer, Jon A. ; Huang, Xiaoxiao ; Ghosh, Rajarshi P. ; Grzybowski, Adrian T. ; Yu, Tao ; Zhang, Qiao ; Riva, Alberto ; Lele, Tanmay P. ; Schatz, George C. ; Kelleher, Neil L. ; Ruthenburg, Alexander J. ; Liphardt, Jan ; Licht, Jonathan D. / A mutation in histone H2B represents a new class of oncogenic driver. In: Cancer Discovery. 2019 ; Vol. 9, No. 10. pp. 1438-1451.
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