A Mutation in Histone H2B Represents a New Class of Oncogenic Driver

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.

Globally altered epigenetic landscape and delayed osteogenic differentiation in H3.3-G34W-mutant giant cell tumor of bone

“…MUT. Besides dominant hypomethylation in heterochromatic regions, we additionally observed profound epigenetic changes at bivalent , iso-H3 3. WT β−value, iso-H3.3Recapitulation of DNA methylation alterations in an isogenic system.…”

“…The discovery of mutated histone genes in aggressive cancers raised a lot of interest in the cancer research community due to their ability to globally alter the epigenomic landscape 1 . A frequently mutated histone is the non-canonical histone variant H3.3 2 , 3 . In contrast to canonical H3.1 and H3.2, the incorporation of histone variant H3.3 is replication-independent and its turnover occurs throughout the cell cycle 4 .…”

Cancer-associated histone mutation H2BG53D disrupts DNA–histone octamer interaction and promotes oncogenic phenotypes

“…In addition to histone H3, two recent reports revealed another class of oncogenic mutation in histone H2B. 7,8 The glutamic acid at position 76 of H2B was found to be replaced by lysine in multiple cancers, including breast and lung carcinomas. Cells expressing the H2BE76K mutation acquired oncogenic phenotypes as a result of aberrant gene expression associated with cancer pathways, an effect possibly due to the destabilization of the histone octamer by H2BE76K.…”

Bringing Oncohistones into the Fold

“…Two recent studies (2, 3), including one published in this issue of Cancer Discovery (2), have added to the list of histone mutations in cancer and confirm an interesting mechanism that was posited by biochemical studies of oncohistones published last year (4). First, using a combination of publicly available datasets and a large single-institution database, Nacev and colleagues identified more than 4,000 missense mutations in histone-encoding genes in samples derived from approximately 3,000 patients (3).…”