Cancer-associated mutations of histones H2B, H3.1 and H2A.Z.1 affect the structure and stability of the nucleosome

Abstract

Mutations of the Glu76 residue of canonical histone H2B are frequently found in cancer cells. However, it is quite mysterious how a single amino acid substitution in one of the multiple H2B genes affects cell fate. Here we found that the H2B E76K mutation, in which Glu76 is replaced by Lys (E76K), distorted the interface between H2B and H4 in the nucleosome, as revealed by the crystal structure and induced nucleosome instability in vivo and in vitro. Exogenous production of the H2B E76K mutant robustly enhanced the colony formation ability of the expressing cells, indicating that the H2B E76K mutant has the potential to promote oncogenic transformation in the presence of wild-type H2B. We found that other cancer-associated mutations of histones, H3.1 E97K and H2A.Z.1 R80C, also induced nucleosome instability. Interestingly, like the H2B E76K mutant, the H3.1 E97K mutant was minimally incorporated into chromatin in cells, but it enhanced the colony formation ability. In contrast, the H2A.Z.1 R80C mutant was incorporated into chromatin in cells, and had minor effects on the colony formation ability of the cells. These characteristics of histones with cancer-associated mutations may provide important information toward understanding how the mutations promote cancer progression.

Evaluation of nucleosome concentrations in healthy dogs and dogs with cancer

“…All samples were tested using the Nu.Q TM H3.1 assay. This is an enzyme-linked immunosorbent assay (ELISA) with a capture antibody directed at histone 3.1 and nucleosome specific detection antibody (18). Assays were performed according to the manufacturer's instructions.…”

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.…”

Gene Expression Signature of BRAF Inhibitor Resistant Melanoma Spheroids

“…Several of these genes are associated with tumour initiation and progression but not well documented at the field of melanoma, however, according to the results of this present study, they might have roles in BRAFi resistance. cBioPortal for Cancer Genomics database supports the idea that seventeen canonical histone H2B genes including HIST1H2B, HIST1H2BM has been found to be involved in cancer progression [44], however no direct role of the genes are described yet. Kim et al reported that CENPF is functionally involved in the tumorigenesis of human cancers and cancer driver genes [52].…”

“…Based on the published data approximately 80% of melanoma cell lines show overexpressed DDAH-1 that represent a potential target for control of nitric oxide production in melanoma cell line [43]. On the other hand suppression of S-phase histone HIST1H2BB can improve treatment outcome in melanoma cells [44]. In contrast, genes that were commonly downregulated in sensitive and resistant melanoma spheroids, including MMP16, IGF1R and FLOT1, are associated with malignancy, and several studies have reported that these genes are related to the aggressive behaviour of melanoma [45,46].…”